Conjugates of lipophilic moieties and fragments of vasoactive intestinal peptide (VIP)

ABSTRACT

The invention concerns novel conjugates of peptide fragments of vasoactive intestinal peptide (VIP) or analogues thereof having 3-12 amino acid residues, and lipophilic moieties, which may be present at the N- or C-terminus. The invention further concerns pharmaceutical compositions containing these novel conjugates which may be used for treatment of male impotence or for the treatment of neurodegenerative diseases.

FIELD OF THE INVENTION

The present invention concerns novel conjugates of a lipophilic moietyand a peptide of 3-12 amino acids. The present invention furtherconcerns pharmaceutical compositions comprising as an active ingredientsaid novel conjugates. The pharmaceutical compositions of the inventionare preferably used for the treatment of male impotence or for thetreatment of neurodegenerative diseases.

BACKGROUND OF THE INVENTION

Vasoactive intestinal peptide (VIP), a 28 amino acid neuropeptide widelydistributed in the mammalian nervous system, has potent neurotrophicactions that influence nerve cell function. In the central nervoussystem, this role of VIP is translated into developmental effects,display of growth factor activities and maintenance of neuronal survivaland function. Neurons, which are capable of releasing VIP, innervateblood vessels throughout the body, as well as the trachea in the lung,and the released VIP serves as a potent vasodilator, inducing smoothmuscle relaxation. Radioligand binding assays, pharmacologicalexperiments, molecular cloning and development of superactive novelderivatives have indicated several classes of VIP receptor sites andseveral potential therapeutical uses.

Two possible therapeutical uses of VIP, modified VIP or lipophilic VIPderivatives were reported in our previous Patents IL 87055, EP 0354992and U.S. Pat. No. 5,147,855 and published patent applications EP 0540969and EP 0620008 which are directed to the treatment of male impotence bytransdermal administration and to the treatment of neurodegenerativediseases, respectively.

VIP is a hydrophilic peptide of a very short half life in the serum(Said, S. I., Editor, Vasoactive intestinal peptide in: Advances inPeptide Hormone Research Series, Raven Press, New York, 1-512 (1982))having the following sequence:

(SEQ ID NO:1)  1   2   3   4   5   6   7   8   9   10  11  12His-Ser-Asp-Ala-Val-Phe-Tyr-Asp-Asn-Tyr-Thr-Arg- 13 14  15   16  17  18  19  20  21  22  23  24Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-  25  25  27  28Ser-Ile-Leu-Asn-NH₂

To enhance its biological availability and increase its stability thepresent inventors have resorted to two chemical modifications reportedin said patents and applications. The first was lipophilization, namely,the addition of a fatty acid moiety, designed to augment VIP's abilityto penetrate biological membranes without loss of activity; thus,stearoyl-VIP, a molecule combining VIP with a stearic acid moiety at itsN-terminal was designed (EP 0354992). The second modification was thereplacement of native amino acids with unnatural amino acids, namely, asubstitution of methionine (amino acid 17 of VIP) by norleucine, aimedat stabilizing the molecule against oxidation as well as at increasinglipophilicity; thus, stearoyl-Nle-VIP was designed (Gozes et al.,Endocrinology, 134:2121-2125 (1994); Fauchere et al., Int. J. PeptideProtein Res., 32:269-278 (1988); EP 0540969). Unmodified VIP fragmentsderived from the 17-24 positions of the VIP sequence are described in EP0225020 as ulcer inhibitors.

A major obstacle in the use of any substance as a medicament is itsdistribution in the body. The modified VIP or lipophilic VIP used fortransdermal treatment of male impotence reported in the abovementionedEP 0354992 and EP 0540969 have to penetrate through the dermis and reachthe erectile tissues in a short a time span as possible.

VIP, modified VIP or lipophilic VIP used to treat neurodegenerativediseases described in EP 0620008 have to pass the blood brain barrier inorder to exert their therapeutic effect on brain cells.

It would have been desirable, both for the purpose of treatment of maleimpotence and for the purpose of administration to the CNS for thetreatment of neurodegenerative diseases, to use molecules that, whilehaving the physiological activity of the full VIP peptide, are smallerin size and thus are able to improve the bioavailability of thetherapeutic compound at the target tissue. Furthermore, smallermolecules are at times more stable to degradation than larger moleculessince, as a rule, they have less sites available to degradation.

SUMMARY OF THE INVENTION

The present invention is based on the surprising finding that shortfragments of VIP or modified VIP conjugated to a lipophilic moiety,which are 3-12 amino acids long, are physiologically active in thetreatment of impotence and/or neurodegenerative diseases. The advantageof using short physiologically active peptides conjugated to alipophilic moiety versus the usage of the full VIP molecule is betterbiodistribution and bioavailability in the body, as well as ease ofpreparation. Furthermore, the invention concerns short cyclic peptidescontaining said short fragments of VIP or of modified VIP conjugated toa lipophilic moiety which in addition to the above advantages featurethe advantage of being relatively degradation resistant.

The present invention is concerned with a conjugate of a peptide coupledto a lipophilic moiety, wherein the peptide has at least 3 and at most12 amino acid residues, said conjugate being selected from the formulae:

(i) R₁-X₁-X₁′-X₁″-X₂-NH—R₂ (SEQ ID NO:2);

(ii) R₁-X₃-Ser-X₄-Leu-Asn-NH—R₂ (SEQ ID NO:3);

wherein

R₁ is H or a lipophilic moiety;

R₂ is H, a lipophililc moiety, a lipophilic moiety substituted byX₃-Ser-X₄-Leu-Asn-NHR₁ (SEQ ID NO:79) or a spacer consisting of 1-3residues of a non-charged amino acid coupled to X₁-X₁′-X₁″-X₂NHR₁ (SEQID NO:80),

with the proviso that at least one of R₁ and R₂ is a lipohilic moiety;

X₁ is a covalent bond, Ala, Val, Ala-Val, Val-Ala, L-Lys, D-Lys,Ala-Lys, Val-Lys, Ala-Val-Lys; Val-Ala-Lys or Orn;

X₁ is L-Lys, D-Lys or Orn;

X₁″ is L-Tyr, D-Tyr, Phe, Trp or the residue of p-amino phenylalanine;

X₄ is Ile or Tyr;

X₅ is a residue of a hydrophobic aliphatic amino acid;

X₂ is X₅, X₅-Asn, X₅-Ser, X₅-Ile, X₅-Tyr, X₅Leu, X₅-Nle, X₅-D-Ala,X₅-Asn-Ser, X₅-Asn-Ser-Ile (residue 1-4 of SEQ ID NO:75), X₅-Asn-Ser-Tyr(residues 1-4 of SEQ ID NO:76); X₅-Asn-Ser-Ile-Leu (residues 1-5 of SEQID NO:75), X₅-Asn-Ser-Tyr-Leu (residues 1‥5 of SEQ ID NO:76),X₅-Asn-Ser-Ile-Leu-Asn (SEQ ID NO:75) or X₅-Asn-Ser-Tyr-Leu-Asn (SEQ IDNO:76);

X₃ is a covalent bond, Asn, X₅, X₅-Asn, Tyr-X₅, Tyr-X₅-Asn, Lys-X₅,Lys-X₅-Asn, Lys-Tyr-X₅, Lys-Tyr-X₅-Asn (residues 4-7 of SEQ ID NO:77),Lys-Lys-Tyr-X₅ ((residues 3-6 of SEQ ID NO:77), Lys-Lys-Tyr-X₅-Asn(residues 3-7 of SEQ ID NO:77), Val-Lys-Lys-Tyr-X₅ (residues 2-6 SEQ IDNO:78), Val-Ala-Lys-Lys-Tyr-X₅-Asn (SEQ ID NO:77), orAla-Val-Lys-Lys-tyr-X₅-Asn (SEQ ID NO:78);

X₆ is a covalent bond or Asn, Ser, Ile, Tyr, Leu, Asn-Ser, Asn-Ser-Ile,Asn-Ser-Tyr, Asn-Ser-Ile-Leu (residues 2-5 of SEQ ID NO:75),Asn-Ser-Tyr-Leu (residues 2-5 of SEQ ID NO:76), Asn-Ser-Ile-Leu-Asn(residues 2-6 of SEQ ID NO:75) or Asn-Ser-Tyr-Leu-Asn (residues 2-6 ofSEQ ID NO:76);

X₇ is a covalent bond or Asn;

X₈ is a covalent bond, X₅, Tyr, Lys, Tyr-X₅, Lys-X₅, Lys-Tyr-X₅,Lys-Lys-Tyr-X₅ (residues 3-6 of SEQ ID NO:77), Val-Lys-Lys-Tyr-X₅(residues 2-6 of SEQ ID NO:78), Ala-Lys-Lys-Tyr-X₅ (residues 2-6 of SEQID NO:77), or Ala-Val-Lys-Lys-Tyr-X₅ (residues 1-6 of SEQ ID NO:78);

Z is —CCNH—, —NHCO—, —S—S—, —S(CH₂)_(t)CO—NH— or —NH—CO(CH₂)_(t)S—;

m is 1 or 2 when Z is —CONH—, —S—S— or —S(CH₂)_(t)CO—NH—, or m is 2, 3or 4 when Z is —NH—CO— or —NH—CO(CH₂)_(t)S—;

n is 1 or 2 when Z is —NH—CO—, —S—S— or —NH—CO(CH₂)_(t)S—, or n is 2, 3or 4 when Z is —CONH— or —S(CH₂)_(t)CO—CO—NH—, and

t is 1 or 2,

with the proviso that the conjugatestearoyl-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:24)is excluded.

The hyrdophobic aliphatic amino acid represented above by X₅ may be aresidue of D- or L- amino acid selected from Ala, Ile, Leu, Met, Val,Nva and Nle.

The term “lipophilic moiety of the conjugates of the invention” willrefer in the following description and claims to: a saturated orunsaturated hydrocarbyl or carboxylic acyl radical having at least 3carbon atoms such as propionyl, caproyl, laurly, palmitoyl, stearoyl,oleyl, eicosanoyl, docsanoyl and the respective hydrocarbyl radicalspropyl, hexyl, dodecyl, hexadecyl, octadecyl, eicosanyl and docosanyl.Preferably the hydrocarbyl or acyl radical is saturated, and has 3-22carbon atoms.

The term “spacer” refers to residue of a non-charged natural ornon-natural amino acid such as alanine, proline and aminocaproic acid.

Examples of the conjugates of the invention are conjungates of alipophilic moiety and peptides of the sequence Lys-Lys-Tyr-Leu derivedfrom position 20-23 of the VIP sequence (SEQ ID NO:1) and/or peptides ofthe sequence Asn-Ser-Ile-Leu-Asn, derived from positions 24-28 of theVIP sequence (SEQ ID NO:1). modified peptides thereof in which aminoacid residues have been replaced, added, deleted or chemically modifiedor combinations of these two sequences such as:

St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6);

St-Lys-Lys-Tyr-D-Ala-NH₂;

St-Ala-Val-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:7);

St-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:8);

St-Lys-Lys-Tyr-Val-NH₂ (SEQ ID NO:9);

St-Ser-Ile-Lau-Asn-NH₂;

St-Lys-Lys-Tyr-Leu-Nle-NH₂ (SEQ ID NO:10);

St-Asn-Ser-Tyr-Leu-Asn-NH₂ (SEQ ID NO:11);

St-Asn-Ser-Ile-Tyr-Asn-NH₂ (SEQ ID NO:12);

St-Lys-Lys-Tyr-Leu-Pro-Pro-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:13;

Lau-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:14);

Cap-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:15);

St-Lys-Tyr-Leu-NH₂;

St-Lys-Lys-Tyr-Nle-NH₂ (SEQ ID NO:16);

St-Val-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:17);

St-Leu-Asn-Ser-Ile-Leu-Asu-NH₂ (SEQ ID NO:18;

St-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:19);

St-Lys-Lys-Tyr-Leu-Asn-NH₂ (SEQ ID NO:20);

St-Lys-Lys-Tyr-Leu-Asn-Ser-NH₂ (SEQ ID NO:21);

St-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-NH₂ (SEQ ID NO:22); and

St-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-NH₂ (SEQ ID NO:23).

In the following, the symbol “St” stands for stearoyl, “Lau” stands forlauroyl and “Cap” stands for caproyl.

By another aspect the present invention concerns pharmaceuticalcompositions comprising as an active ingredient, active conjugates ofthe invention together with a pharmaceutically acceptable carrier.

The pharmaceutical composition of the invention comprising a conjugateof the invention or the conjugateSt-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:24)(hereinafter “Peptide”) described in EP 0620008 may be used for thetreatment of sexual disfunctions such as male impotence, preferably bytransdermal or urinary tract application. Preferred conjugates used forthis purpose are:

St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6);

St-Lys-Lys-Tyr-D-Ala-NH₂;

St-Ala-Val-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:7);

St-Asn-Ser-Ile-Leu-Asn-NH₂;

St-Lys-Lys-Tyr-Val-NH₂ (SEQ ID NO:9);

St-Ser-Ile-Lau-Asn-NH₂;

St-Asn-Ser-Tyr-Leu-Asn-NH₂ (SEQ ID NO:11);

St-Asn-Ser-Ile-Tyr-Asn-NH₂;

St-Lys-Lys-Tyr-Leu-Nle-NH₂ (SEQ ID NO:10); and

St-Lys-Lys-Tyr-Leu-Pro-Pro-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:13).

The pharmaceutical compositions of the invention may also be used forthe treatment of neurodegenerative diseases, such as Alzheimer, DownSyndrome, hypoxia, decline in motor or cognitive function due toischemia, stroke, hereditary diseases of the central and peripheralnervous system, decline in motor or cognitive function due to injury ofthe central or peripheral nervous system, decline in cognitive functionsdue to old age and neurological disorders associated with bloodcirculation and neuronal survival. The term “treatment” should beunderstood in the context of the present invention as alleviation,improvement or abolishment of the abnormal conditions manifested inthose diseases and more particularly to improvement in cognitivefunctions damaged by those diseases. Preferred conjugates used for thispurpose are:

St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6);

St-Lys-Lys-Tyr-D-Ala-NH₂;

St-Ala-Val-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:7);

St-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:8);

St-Lys-Lys-Tyr-Val-NH₂ (SEQ ID NO:9);

St-Ser-Ile-Lau-Asn-NH₂;

Lau-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:14);

Cap-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:15);

St-Lys-Tyr-Leu-NH₂;

St-Lys-Tyr-Leu-NH₂;

St-Lys-Lys-Tyr-Nle-NH₂ (SEQ ID NO:16);

St-Val-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:17);

St-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:18);

St-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:19);

St-Lys-Lys-Tyr-Leu-Nle-NH₂ (SEQ ID NO:10);

St-Lys-Lys-Tyr-Leu-Asn-NH₂ (SEQ ID NO:20);

St-Lys-Lys-Tyr-Leu-Asn-Ser-NH₂ (SEQ ID NO:21);

St-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-NH₂ (SEQ ID NO:22); and

St-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-NH₂ (SEQ ID NO:23).

Optional modes of administration of pharmaceutical compositions of theinvention are subcutaneous, intravenous, oral, nasal, ocular, by anintracerebroventricular pump, through the urinary tract or transdermaladministration.

Where the pharmaceutical compositions of the invention are used to treatimpotence, urinary tract or transdermal administration are preferable.For transdermal application the carrier is preferably selected fromamongst those which enhance the tissue penetration of the activeingredient. Examples of suitable carriers are olive oil, glycerine,lubricants, nitroglycerin and Sefso™, and mixtures thereof. Sefsol is atrademark (Nikko Chemicals, Tokyo) for, 1-glyceryl monocaprylate,propylene glycol didecanoate, propylene glycol dicaprylate, glyceryltricaprylate and sorbitan monocaprylate and they are the preferredcarriers in compositions according to the invention. Of these,1-glyceryl monocaprylate and olive oil are particularly preferred. Forurinary tract application a gel is preferably used as a carrier.

The present invention further provides, for the sustained release of aconjugate of the invention, a transdermal dispenser comprising anapplicator loaded with said conjugate and adapted for application to theskin.

If desired, the conjugate in the applicator may be formulated into apharmaceutical composition of the kind specified above.

Treating male impotence by transdermal administration exhibits severaladvantages over modes of parenteral, such as subcutaneous,administration. For one, it is non-surgical and does not entail tissuedestruction. Moreover, it does not cause priapism or the burning painassociated with other modes of administration. Furthermore, thetransdermal application is a much more discreet and convenient mode ofapplication as compared to an intracavernosal injection. Transdermaladministration enables the use of a continuous slow release device whichmay enable spontaneous sexual activity without the need for a lengthypreparation, thus sparing an inflicted individual much of the usualembarrassment.

Where the pharmaceutical compositions of the invention are to be used asdrugs acting on the central nervous system, it is preferable toadminister them through the nose, which enables the penetration of theaerosol composition to the CNS through the olfactory nerve (WO91/07947), via the ocular route (Chiou, G. C. Y., (1991) An. Rev.PharmacoL Toxical., 31:457-67) or by any other suitable method ofadministration as described in W. M. Pardridge, Peptide Drug Delivery,Raven Press, N.Y. 1991.

The pharmaceutical compositions of the invention may be also directlytargeted to the brain by an intracerebroventricular pump.

The present invention further concerns a method of treatment ofneurodegenerative diseases or male impotence by administering to a hostin need of such treatment a therapeutically effective amount of theconjugate of the invention.

The present invention still further provides use of the conjugate of theinvention for the preparation of a pharmaceutical composition.

As will be appreciated by any person versed in the art, the conjugatesas defined above in formulae I above include a large number of possibleconjugates. Those which fall under the scope of the invention and thosedefined as “active conjugates” in the pharmraceutical composition of theinvention are the conjugates which are active in at least one of thefollowing assays:

(1) conjugates which are able to induce erection in an animal model ofimpotence (normal and castrated animals);

(2) conjugates which have the activity of protecting electricallyblocked neurons from death;

(3) conjugates which are able to protect untreated neurons in culturefrom naturally occurring death;

(4) conjugates which are able to protect cultured neurons from deathcaused by a 25-35 fragment of β-amyloid peptide;

(5) conjugates which are able to avoid deterioration of learning andmemory acquisition of either old animals or animals treated with adementia causing agent as tested in an acceptable learning of memoryacquisition assay, as well as conjugates which are able to improverecollection of a previously acquired task in animals treated with adementia causing agent, for example, as described in example.

(6) conjugates which are able to avoid or ameliorate decline of motorand cognitive functions in an animal model of ischemia and/or models ofstroke;

(7) conjugates which are able to protect neurons from damage caused dueto lack of oxygen;

(8) conjugates which are able to improve motor and cognitive functionsin models for hereditary neurodegenerative diseases of the central andperipheral nervous system such as models of mice with a knock out ofApoE (Cell, 71:343 (1992)); transgenic models of amyloid over-expression(Nature, 373:523 (1995)); models for ALS which are mutant super oxidedismutase expression (Science, 264, 1772 (1994)) and a model for DownSyndrome which is trisomy of chromosome 16; and

(9) conjugates which are able to improve motor and cognitive functionsin models of injury of the central and peripheral nervous system such aslesions of the nucleus basalis in rats (PNAS, 85:9481 (1988));scopolamine-induced acetylcholine release in ventral hippocampus (PNAS,90:11287 (1993)); NMDA induced convulsions (Brain Res. 448:115 (1988)).

In the following, the invention will be further illustrated withreference to some non-limiting drawings and examples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of varying concentrations ofSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) on the survival of neurons treatedwith β-amyloid peptide;

FIG. 2 shows the effect of the cholinergic blocker AF64A (◯) and ofAF64A together with St-Lys-Lys-Tyr-Leu-NH₂ SEQ ID NO:6) () on learningand memory in an animal model of Alzheimer;

FIG. 3 shows the effect of the cholinergic blocker AF64A (e) and ofAF64A together with St-Lys-Lys-Tyr-D-Ala-NH₂ (▴) on learning and memoryin an animal model of Alzheimer;

FIG. 4 shows the effect of administration of saline control (◯); salinetogether with St-Lys-Lys-Tyr-D-Ala-NH₂ (▪); the cholinergic blockerAF64A (▴) and AF64A together with St-Lys-Lys-Tyr-D-Ala-NH₂ (♦) on memoryretention in an animal model of Alzheimer;

FIG. 5 shows motor function of animals treated with saline (); salineand St-Lys-Lys-Tyr-D-Ala-H₂ (▪); the cholinergic blocker AF64A (▴) andanimals treated with AF64A together with St-Lys-Lys-Tyr-D-Ala-NH₂ (♦);

FIG. 6 shows the effect of administration of saline (◯) and theconjugate St-Lys-Lys-Tyr-D-Ala (□) on learning and memory in normalcontrol animals administered with the vehicle;

FIG. 7 shows the effect of administration of saline (); saline andSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) (▪); the cholinergic blocker AF64A(▴) and AF64A together with St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) (♦) onmemory retention of a previously learned task in an animal model ofAlzheimer (first swim);

FIG. 8 shows the same experiment as described in connection with FIG. 7for the second swim including administration of saline andSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6); and of AF64A together withSt-Lys-Try-Leu-NH₂ (SEQ ID NO:6);

FIG. 9 shows the same experiment as described in connection with FIG. 7measuring the time spent by the animals in the area where the platformused to be;

FIG. 10 shows the effect of St-Lys-Lys-Tyr-Leu-NH₂ (St-KKYL-NH₂ (SEQ IDNO:6) and saline on forelimb placing behavior acquisition in normalnewborn mice (St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) (▴); saline (◯)), andon ApoE deficient newborn mice (APO E); (St-Lys-Lys-Tyr-Leu-NH₂ (SEQ IDNO:6) (▴); saline ()).

FIG. 11 shows for comparison the effect of St-Nle¹⁷-VIP-NH₂ and salineon forelimb placing behavior acquisition in normal newborn mice(St-Nle¹⁷-VIP-NH₂ (▾); saline (), and on ApoE deficient newborn mice(St-Nle¹⁷-VIP-NH₂ (▴); saline (♦));

FIG. 12 shows the effect of St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6)(St-KKYL-NH₂) and saline on cliff avoidance acquisition in normalnewborn mice (St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6), (▾); saline. ());and ApoE deficient mice (St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) (▴);saline (♦));

FIG. 13 shows for comparison the effect of St-Nle¹⁷-VIP-NH₂ on cliffavoidance acquisition in normal newborn mice and ApoE deficient mice;

FIG. 14 shows the Choline Acetyl transfcrasc activity of control, andApo-E deficient mice treated with St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6);

FIG. 15 shows the HPLC analysis of brain extracts of rats intranasallyadministered with ¹²⁵I-St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6);

FIG. 16 shows the effect of St-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:24) (peptide 6) in DMSOon the number of E2 and cups;

FIG. 17 shows the effect ofSt-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:24)(peptide 6) and of St-Ala-Val-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:7) (peptide26) in DMSO on the number of cups and on the number of E2;

FIG. 18 shows the effect of St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) in 5%Sefsol™/20% isopropanol on the number of cups and on the number of E2(C=vehicle control; E=experimental peptide);

FIG. 19 shows the effect of St-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:25) inSefsol™/isopropanol on the number of cups and on the number of E2(C=vehicle control; E=experimental peptide);

FIG. 20 shows the effect of St-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:8) inSefsol™/isopropanol on the number of cups and on the number of E2(C=vehicle control; E=experimental peptide);

FIG. 21 shows the effect of St-Asn-Ser-Ile-Tyr-Asn-NH₂ (SEQ ID NO:22) inSefsol™/isopropanol on the number of cups and on the number of E2(C=vehicle control; E experimental peptide);

FIG. 22 shows the effect of St-Asn-Ser-Tyr-Leu-Asn-NH₂ (SEQ ID NO:11) inSefsol™/isopropanol on the number of cups and on the number of E2;

FIG. 23 shows the effect of St-Lys-Lys-Tyr-D-Ala-NH₂ (KKYO) andSt-Lys-Lys-Tyr-Val-NH₂ (KKYV) (SEQ ID NO:9) on the number of cups;

FIG. 24 shows the effect of St-Lys-Lys-Tyr-D-Ala-NH₂ (KKYO) andSt-Lys-Lys-Tyr-Val-NH₂ (KKYV) (SEQ ID NO:9) on the latency to the firstcup;

FIG. 25 shows the effect of St-Lys-Lys-Tyr-D-Ala-NH₂ (KKYO) andSt-Lys-Lys-Tyr-Val-NH₂ (KKYV) (SEQ ID NO:9) on the number of E2;

FIG. 26 shows the effect of St-Lys-Lys-Tyr-Leu-Nle-NH₂ (SEQ ID NO:10) onthe number of cups;

FIG. 27 shows the effect ofSt-Lys-Lys-Tyr-Leu-Pro-Pro-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:13) on thenumber of cups;

FIG. 28 shows biodistribution following topical administration of¹²⁵I-St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6);

FIG. 29 shows the HPLC analysis of intestinal extract of animalstopically administered with ¹²⁵I-St-Lys-Lys-Tyr-Leu-NH₂ (St-KKYL-NH₂)(SEQ ID NO:6); and

FIG. 30 shows the effect of injection into the corpus cavernosum tovehicle, 0.1 μg of St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6), and 10 μgSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) on penile blood pressure.

DETAILED DESCRIPTION OF THE INVENTION

A. Synthesis of Linear Peptides

To obtain a large battery of small peptides an automatic peptidesynthesizer was utilized. Syntheses of the peptides of the inventionwere achieved by automatic procedure employing an ABIMED AMS 422synthesizer (ABIMED, Langenfeld, Germany) using the commerciallyavailable protocols via the Fmoc strategy. All protected amino acidderivatives were as recommended by the company. Thus, the followingside-chain protection was utilized: Lys, N-epsilon-t-butyloxycarbonyl(Boc), Tyr, Thr, Ser, O-t-butyl; Arg;2,2,5,7,8-pentamethylchroman-6-sulfonyl (PMC); Trp, N^(int)-Boc; Cys,S-trityl, Asn, beta-trityl, PyBOP, i.e.benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate,was used as a coupling agent. Peptide chains were assembled on a4-([2″,4″-dimethoxyphenyl] Fmoc aminoethyl) phenoxy resin (Rink amideResin, Nova, Switzerland).

Final cleavage of the peptide chain from the resin along with the sidechain deprotection was achieved as follows: cleavage mixture: 90% TFA,5% water, 5% triethylsilane. The resin, 100 mg, loaded with peptide wasincubated for 30 min with a 3 ml cleavage mixture inside the reactioncolumn used for solid phase synthesis. After 30 min, the reaction wasseparated from the cleaved resin and cleavage continued for anadditional 3 hrs. The cleaved peptide was precipitated with ice coldtert-butylmethyl ether and centrifuged (4° C., 2000 rpm). To ensureoptimal precipitation, petroleum ether (b.p. 40-60° C., 1:1 v/v) wasoccasionally added. The solution was decanted and the pellet wasdissolved in water and frozen for lipophilization to yield a whitepowder. Purification of the crude peptides was performed bysemi-preparative HPLC on an RP-8 column (Merck 7 μM; 250×10 mm)employing linear gradient established between 35% acetonitrile in watercontaining 0.1% TFA, and 0.1% TFA in 75% acetonitrile in water at a flowrate of 10 m/min. Elution was monitored at 220 nm. Yields were 30-45%.Purity of the products was ascertained by analytical HPLC on an RP-18column (Merck; 250×4 mm) and amino acid analysis following exhaustiveacid hydrolysis gave the expected values of each constituent amino acid.

Examples of the conjugates comprising linear peptides that weresynthesized by this method are those listed on pages 5-9 hereinbeforeand the following conjugates are:

SEQ. SEQ. ID. ID. NO: NO:  1. CapKKYLZZ* 26 29. StYLNSILN* 19  2.LauKKYLZ* 27 30. StKKYLNle* 10  3. KKYLZ* 28 31. StKKYLO* 49  4. KKYLZZ*29 32. StKKYLL* 50  5. KKYLB* 30 33. StKBYL* 51  6. KKYLZZZ* 31 34.StBKYL* 52  7. LauNSILNZ* 32 35. StBBYL* 53  8. NSILNZ* 33 36. StKKFL*54  9. NSILNZZ* 34 37. StKKOL* 10. CapNSILNZZ* 35 38. StKKYZ* 55 11.NSILNZZZ* 36 39. StKKWL* 56 12. NSILNB* 37 40. StKKXL* 57 13.KKYLZNSILN* 38 41. StKOrnYl* 58 14. KKYLZZNSILN* 39 42. StOrnKYL* 59 15.KKYLZZZNSILN* 40 43. StOrnOrnYL* 60 16. KKYLBNSILN* 41 44. OIKKYL* 6117. StKKYLXXXNSILN* 42 45. PropylKKYL* 62 18. StKKLYAAANSlLN* 43 46.StKKYLAAKKYL* 63 19. StKKYLPNSILN* 44 47. StKKYLPPKKYL* 64 20.StKKYLPPNSILN* 13 48. StKKYLAcaKKYL* 65 21. StKYLNSILN* 45 49.StKKYLAm.Lauryl 66 KKYL* 22. StKKYLNSILN* 46 50. StKKYLNle* 10 23.StKKYLN* 20 51. StKKYLdA* 24. StKKYLNS* 21 52. StKKYLL* 67 25.StKKYLNSI* 22 53. CapKKYL* 15 26. StKKYLNSIL* 23 54. LauKKYL* 14 27.LauKKYLNSILN* 47 55. CapNSILN* 68 28. StKYLN* 48 56. LauNSILN* 69

wherein Cap=Caproic acid, Lau=Lauric acid, St=Stearic acid;Z=Aminocaproic acid, B=Aminolauric acid, X=d, lAla, O=D-Ala; B=dK, O=dY,Z=dL, X=p=aminoPhe, *=amid, Ol=Oleic acid

B. Synthesis of Cyclic Peptides

I. Cyclic peptides containing intramolecular amide bonds, i.e. Z=—CONH—or —NHCO— of the formulae III and IV as defined above may be preparedthrough conventional solid phase synthesis. Thus, peptide chains may beassembled on the solid support while incorporating suitable amino andcarboxyl side-chain protected amino acid derivatives at the positionsselected for cyclization. Following completion of peptide chainassembly, the protecting groups can be selectively removed from thecorresponding amino and carboxyl functions, leaving other protectinggroups and the peptide-support bond intact. Cyclization can then beaccomplished using known peptide coupling agents. Finally, the cyclicpeptide may be cleaved from the support along with deprotection of sidechain moieties using known procedures, and purification of the desiredcyclic peptide can be achieved by chromatographic techniques.

II. Cyclic peptides containing an intramolecular disulfide bond, i.e.Z=S—S of the formulae III and IV as defined above may be preparedthrough conventional solid phase synthesis while incorporating suitableS-protected cysteine or homocysteine residues at the positions selectedfor cyclization. Following completion of the chain assembly, twopossible routes for cyclization can be performed: 1. Selective removalof S-protecting groups with a consequent on-support oxidation of freecorresponding two SH-functions, to form S′—S bonds. This may be followedby conventional removal of the product from the support and appropriatechromatographic purification. 2. Removal of the peptide from the supportalong with complete side-chain deprotection, followed by oxidation offree SH-functions in highly dilute aqueous solution. Both routes lead tothe same final desired product.

III. Cyclic peptides containing intramolecular S-alkyl bonds, i.e.Z=—S(CH₂)_(t)CO—NH or —NH—CO(CH₂)_(t)S— of the formulae III and IV asdefined above may be prepared through conventional solid phasesynthesis. Thus, an amino acid residue with a suitable amino-protectedside chain, and a suitable S-protected cysteine or homocysteine residuemay be incorporated during peptide chain assembly at positions selectedfor cyclization. The blocked side-chain amino function is selectivelydeprotected followed by bromoacylation. The peptide can then be detachedfrom the support, along with side-chain deprotection, under acidicconditions. Under neutral or slightly basic conditions, thecorresponding free SH and bromoacylated moieties may then selectivelyinteract at high dilution to afford the desired cyclic peptide.

EXAMPLE B1

[General formula (iii) above wherein X₅=Leu; X₆=covalent bond;Z=—NH—CO—; m=4, n=1]

Synthesis of the peptide is performed manually on ap-amethylbenzhydrylamine (MBHA) resin available from Nova, Switzerland.All solvents, methylene chloride (CH₂Cl₂), N-methylpyrrolidone (NMP) anddimethyl sulfoxide (DMSO) are analytical products of Merck, Germany.Trifluoroacetic acid (TFA), diisopropylethylamine (DIEA) andN,N′-dicyclohexylcarbodiimide (DCC) are purchased from Aldrich, U.S.A.1-Hydroxybenzotriazole (HOBT) is obtained from Nova, Switzerland. Allprotected amino acid derivatives (Boc-AA) are of the L-configuration andare obtained from Bachem, Switzerland. Nα-amino acid functions areprotected throughout the synthesis by the t-butyloxycarbonyl (t-Boc)group. Side chain functions are protected as follows: Asp with9-fluorenylmethyl (Fm), Lys with 2-chloro-benzyloxycarbonyl, and atposition 1 of the peptide chain with 9-fluorenylmethoxycarbonyl (Fmoc)and Tyr with 2,6-dichlorobenzyl.

The synthesis is initiated by coupling Boc-Asp (OFm) (0.82 g, 2 mmol) tothe methylbenzhydryl amine resin (1 g) using DCC (0.42 g, 2 mmol) andHOBT (0.272 g, 2 mmol) as reagents. Loading (0.39 mmol/g) is determinedby amino acid analysis. Unreacted residual amino groups on the polymerare capped by reacting with acetic anhydride and triethylamine (20 mland 0.5 ml, correspondingly) in CH₂Cl₂ (10 ml). The peptide chainassembly is started with the Boc-Asp(OFm)-MBHA resin, following theprotocol outlined in Table 1.

TABLE 1 Protocol for manual solid phase synthesis. Step Reagent/SolventsTime (min.) 1 TFA in CH₂Cl₂ (30% v/v) 3 2 ThA in CH₂Cl₂ (50% v/v) 20 3CH₂Cl₂ 5 × 2 4 3% DIEA in CH₂Cl₂ (v/v) 5 5 3% DIEA in NMP (v/v) 2 6 NMP5 × 2 7 Ninhydrin test 8 1.6 mmol Boc A.A. + 1.6 ml 1N 45 HOBT + 1.6 ml1N DCC all in NMP; preactivation - 30 min; filter and add solution topolymer (1 g) 20 DMSO (final vol. 20% v/v) 9 DIEA (6 mmol in NMP) 10 10NMP 5 11 CH₂Cl₂ 3 × 2 12 Ninhydrin test 13 10% Ac₂O + 3% DIEA in CH₂Cl₂5 14 10% Ac₂O in CH₂Cl₂ 10 15 CH₂Cl₂ 3 × 2

Solvents for all washings and reactions are measured to volumes of 10ml/g resin. All couplings are performed using HOBT active esters ofBoc-amino acid derivatives, prepared by DCC prior to each coupling step.A molar ratio of 4:1 of Boc-amino acid 1-hydroxybenzotriazole ester(Boc-AA-OBT) and α-amino group of a growing peptide chain, respectively,is employed for couplings. Coupling reactions are monitored by boiling afew mg (⁻3) of polymer in a solution of ninhydrin in pyridine-water for2 min. Coupling of Boc-amino acids is repeated twice to ensure completereaction. In the second coupling, half of the amount of Boc-AA OBT isused. As a rule, after completion of each coupling step, residual aminogroups are capped by treating the resin with acetic anhydride (10%) anddiisopropylethylamine (3%) in methylene chloride, followed by treatmentwith 10% acetic acid in methylene chloride.

Following completion of the peptide chain assembly, the t-Boc protectinggroup of Lys-1 is removed, as usual, by 50% TFA in CH₂Cl₂ and the newlyfree α-amino group is coupled to stearic acid (0.37 g, 2 mmol) using DCC(0.42 g, 2 mmol) and HOBT (0.27 g, 2 mmol) as reagents (Protocol). Thereaction proceeds for 120 min and is repeated twice. The OFm and Fmocside-chain protecting group of Asp⁶ and Lys¹, respectively, are removedusing 50% piperidine in DMF for 1 hr. Following extensive washings withDMF (3×10 ml), dichloromethane (3×10 ml), 10% DIEA in CH₂Cl₂ (3×10 ml),DMF (3×10 ml) and CH₂Cl₂ (3×10 ml), the resin is suspended in 7 ml DMFand mixed with five-fold excess (2 mmol) of(benzotriazolyloxy)tris(dimethyl)aminophosphonium hexafluorophosphate(BOP) reagent in the presence of seven-fold excess (2.8 mmol) of DIEAfor 8 hr. Cyclization is repeated following the exact procedure. Anegative ninhydrin test indicates completion of cyclization. The fullyassembled cyclic peptide-resin is washed with CH₂Cl₂ according toprotocol, then dried under vacuum overnight, over P₂O₅. Deblocking ofprotecting groups and cleavage of the peptide from resin is achieved bythe anhydrous HF technique. Thus, the peptide-resin (1 g) is treated ina Teflon™ HF apparatus (Multiple Peptide System) with 9 ml HF in thepresence of a mixture of 1.5 ml of p-thiocresol and p-cresol (1:1 v/v)for 1 hr at 0° C. The HF is removed by vacuum and the resin is extractedwith peroxide-free ether (4×25 ml), filtered, dried and extracted with50% acetic acid in water (3×25 ml). Lyophilization of aqueous filtrateyielded the crude powder of

The crude product was dissolved in 50% aqueous acetic acid and passedthrough a Sephadex G-25 column (75×2 cm) employing 0.1 N acetic acid asan eluent. Elution was monitored spectrophotometrically at 274 nm.Lyophilization of the aqueous solution yielded the peptide free ofaromatic additives added as scavengers at the HF-cleavage step. Yieldwas 50-70%.

Purification by high performance liquid chromatography (HPLC) is thencarried out on the Sephadex-fractionated products. This can beperformed, however, on the crude peptide. Purifications were achieved ona Merck RP-8 column (7 μM, 250×10 mm). The peptide is applied in 10%acetonitrile in water and eluted with a linear gradient establishedbetween 0.1% TEA in water and 0.1% TFA in 75% acetonitrile in water at aflow rate of 10 ml/min. Fractions are collected and cuts made afterinspection by analytical HPLC. Derived fractions are pooled andlyophilized. Yield of the pure peptide is 30-35%.

Purity of the product is ascertained by analytical HPLC (Merck RP-8,250×4 mm column) and amino acid analysis, following exhaustive acidhydrolysis (6 N HCl), which gives the expected values of eachconstituent amino acid.

Other related cyclic derivatives of formulae (iii) and (iv) abovewherein Z is —NH—CO— or —CO—NH— are prepared by exactly the same processwhile employing the corresponding amino acid derivatives.

Alternatively, the cyclic derivatives may be prepared by the processesdescribed above and then the stearoyl or other suitable lipophilicmoiety is introduced into the molecule at the N terminal.

EXAMPLE B2

[General formula (iii) above wherein X₅=Leu, X₆ is a covalent bond,Z=—S—S—; n=1, m=1]

Synthesis of the peptide is performed manually on ap-methylbenzhydrylamine (MBHA) resin (1 g) as outlined in the previousexample. Cysteine residues, 1 and 6, are introduced into the peptidechain employing Boc-Cys(S-4-MeBzl)—OH as a building block. Followingcompletion of the chain assembly and addition of N-terminal stearoylmoiety, the peptide-resin is treated with anhydrous HF as describedabove. The white powder of crude peptide obtained after lyophilizationis dissolved in 0.1% acetic acid (⁻0.5 mg/ml) and the solution isde-aerated by bubbling through oxygen-free nitrogen for 2 hr. The pH ofthe solution is adjusted with concentrated aqueous NH₄OH to ˜8.5 and asolution (˜1 N) of K₃Fe(CN)₆ (2.5 equiv.) in water is slowly addeddropwise. After complete addition of the oxidant reagent, the reactionmixture is allowed to stir for ˜1 hr at room temperature. The solutionis then concentrated by rotary evaporation and the crude cyclic productis fractionated on Sephadex G-25, as described above. Purification isthen achieved by HPL-C on a Merck RP-8 column (see previous example).Yield of the pure product is 35-40%. Other cyclic peptides containingS—S internal bridges are prepared following the above procedure whileemploying Boc-Cys(S-4-MeBzl)-OH and Boc-Homocys(S-4-MeBzl)-OH asbuilding blocks, which are introduced at sites selected for cyclization.

EXAMPLE B3

[General formula (iii) above wherein X₅=Leu; X₆=covalent bond:Z=—S—(CH₂)_(t)—CO—NH—; m=1; n=4; t=1]

Synthesis of the peptide is performed manually on ap-methylbenzhydrylamine (MBHA) resin (1 g) as outlined in the previousexample. A cysteine residue 1 is introduced into the peptide chainemploying Boc-Cys(S-4-MeBzl)-OH, while Lys-6 is introduced asBoc-Lys(ε-Fmoc)-OH. Following completion of the chain assembly andaddition of N-terminal stearoyl moiety, the ε-Fmoc protecting group ofLys-6 is removed by treatment with 20% piperidine in DMF for 30 min.Extensive washings of the resin are then performed with DMF (3×10 ml),CH₂Cl₂ (3×10 ml), 10% DIEA in CH₂Cl₂ (3×10 ml), DMF (3×10 ml) and CH₂Cl₂(3×10 ml). The resin is suspended in 10 ml of DMF and mixed withfive-fold excess (2 mmol) of bromoacetic acid anhydride for 6 hr. Theresin is washed with DMF (3×10 ml) and the reaction repeated. Negativeninhydrin test indicates completion of the acylation reaction. The resinis then washed with DMF (3×10 ml), and CHCl₂ (3×10 ml), dried in vacuoand treated with anhydrous HF using anisole (10%) as the only scavenger.A crude bromoacetylated product is obtained using the same manipulationsdescribed in previous examples. The white powder (˜0.5 mg/ml) is thendissolved in 0.1% acetic acid and the pH is adjusted to ˜7.0 by 1 NNaOH. After reacting for 4 hr at room temperature, the solution, devoidof free SH-functions as indicated by Ellman's Reagent (Aldrich), isconcentrated by rotary evaporation. The crude product is then purifiedby being passed through a Sephadex G-25 column, followed by preparativeHPLC, as described in Example A. Yield of the pure product is 25-30%.Other cyclic peptides containing internal —S—(CH₂)_(t)—CO—NH— or—NH—CO—(CH₂)_(t)—S— bridges are prepared following the above procedurewhile employing, at the site selected for cyclization and elsewhere, thecorresponding amino acid derivatives.

C. The Neurodegenerative Treatment Aspen of the Invention

EXAMPLE C1

Biological Test—Effect of Conjugates of the Invention on the Survival ofβ-Amyloid Peptide Treated Neurons

Method

β-Amyloid peptide is known to be involved in Alzheimer's disease and isa toxic substance to neurons grown in culture (Pike et al., J. ofNezarosci., 13(4), 1676-1687 (1993); Yankner et al., Science,250:279-282 (1990); Gozes et. al., Proc. Natl. Acad. Sci. USA,93:927-432 (1996)).

Rat cerebral cortical cell cultures were prepared by a slightmodification of the techniques described by Forsythe and Westbrook (J.Physiol. Lord. 365:515, (1988)), in which cerebral cortex was usedinstead of hippocampus and newborn rats were utilized instead of E16mice. Cerebral cortical cells (1.5-15×10⁵ cells/35 mm dish) were platedon confluent cerebral cortical astrocyte feeder cultures as described(Gozes et al., J. Pharmacol Erp. Therap., 257:959-966 (1991)). Theculture medium was DMEM-(Dulbeco Modified Eagle Medium) containing 5%horse serum and N3 [media supplement containing a hormone cocktail,according to (Romijn et al., Brain Res., 254:(4),583-589 (1981))]. Aftereight days growth in vitro, the cultures were given a complete change ofmedium and then were treated with the β-amyloid peptide (amino acids25-35) for 5 days.

The β-amyloid peptide fragment was dissolved in water to afinalconcentration of 2.5 mM. Experiments were performed withincreasing, doses of the conjugates of the invention (1 mg initiallymixed with 10 μl DMSO and then with a further 10 μl of DMSO to achievecomplete solubilization and diluted in PBS to obtain a stock solution of10⁻³ M) that were added together with 25 μM β-amyloid peptide (aminoacids 25-35) to dissociated cerebral cortical cells, nine days afterplating of neurons. Ten μl of conjugate solution was added to 1 mlculture medium. The duration of treatment was 5 days with no change ofmedia. After 14 days in culture, cells were fixated forimmunocytochemistry and stained with antibodies against NSE (neuronspecific enolase, a neuronal marker). Neuronal cell counts were executedon 60 fields. with a total area of 25 mm². Neurons were counted withoutknowledge of type of treatment as before. Each value is the mean±SEM of3 dishes.

The results are shown in FIG. 1 and Table 2. FIG. 1 shows the summationof five independent experiments, with the control containing 164, 225,130, 319, 172 neurons. As can be seen in FIG. 1, St-Lys-Lys-Tyr-Leu-NH₂is a very active conjugate exhibiting activities at 10⁻¹³−10⁻⁹ M with apeak activity at 10⁻¹²−10⁻¹⁰ M. The cell count of cells treated withboth this conjugate and β-amyloid peptide was higher than the counts ofuntreated control cells indicating that this conjugate was able toprotect cells also against naturally occurring death.

TABLE 2 Peptide Activity in the neuronal survival assay, protectionagainst β-amyloid toxicity: SEQ. ID Active Neuronal % survival afterConcentration Peptide NOS concentration (M) survival (%) β-amyloidtested  1 St-Lys-Lys-Tyr-Leu-NH₂  6 10⁻¹³-10⁻⁹  80-110 52 10⁻¹³-10⁻⁹ 2St-Lys-Lys-Tyr-Val-NH₂  9 10⁻¹³ 72 38 10⁻¹³-10⁻⁹ 3St-Lys-Lys-Tyr-D-Ala-NH₂ 10⁻¹⁵-10⁻¹²  67-117 44 10⁻¹⁵-10⁻¹¹ 4St-Lys-Lys-Tyr-Nlc-NH₂ 16 10⁻¹⁴-10⁻¹² 76-84 44 10⁻¹⁵ 10⁻¹¹ 5Lau-Lys-Lys-Tyr-Leu-NH₂ 14 10⁻¹¹-10⁻¹⁰ 83-84 63 10⁻¹³-10⁻⁹ 6Cap-Lys-Lys-Tyr-Leu-NH₂ 15 10⁻¹¹ 73 63 10⁻¹³-10⁻⁸ 7 St-Lys-Tyr-Leu-NH₂10⁻¹¹ 96 53 10⁻¹³-10⁻⁹ 8 St-Val-Lys-Lys-Tyr-Leu-NH₂ 17 10⁻¹²-10⁻⁸ 70-9253 10⁻¹³-10⁻⁸ 9 St-Lys-Lys-Tyr-Leu-Nle-NH₂ 10 10⁻¹³-10⁻¹⁰  95-100 3610⁻¹³-10⁻⁹ 10 St-Lys-Lys-Tyr-Leu-Asn-NH₂ 20 10⁻¹³-10⁻¹⁰ 52-73 34-5710⁻¹³-10⁻⁹ 11 St-Lys-Lys-Tyr-Leu-Asn-Ser-NH₂ 21 10⁻¹³ 83 52 10⁻¹³-10⁻⁹12 St-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-NH₂ 22 10⁻⁹ 123  57 10⁻¹³-10⁻⁹ 13St-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-NH₂ 23 10⁻⁹ 97 57 10⁻¹³-10⁻⁹ 14St-Asn-Ser-Ile-Leu-Asn-NH₂  8 10⁻¹¹ 10⁻¹⁰  68-103 40 10⁻¹³-10⁻⁹ 15St-Ser-Ile-Leu-Asn-NH₂ 25 10⁻¹²-10⁻⁹ 84-58 40 10⁻¹³-10⁻⁹ 16St-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ 73 10⁻¹³-10⁻¹¹ 100-114 58 10⁻¹³-10⁻⁹ 17St-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ 19 10⁻¹³-10⁻¹¹  88-110 58 10⁻¹³-10⁻⁹

As can be seen in Table 2, several modifications of theSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) conjugate (1) showed similaractivity in protection of neurons from death caused by β-amyloid ascompared to control. In some cases (where neuronal survival exceed 100%as compared to control) the conjugates were able to protect also againstnaturally occurring death. Notably substitution of Leu of conjugate 1 byVal (3), D-Ala (3), Nle (4), addition of amino acid residues at theN-terminal (8) or C-terminal (9,10,11,12,13), deletion of amino acidresidues from the N-terminal (7) or replacement of the lipophilic moietyStearoyl by Lauroyl (Lau), (5) or Caproyl (Cap,6) resulted in conjugateswith activity similar to St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6).

EXAMPLE C2

Effects of a Conjugate of the Invention on Learning and Memory in AnimalModels of Alzheimer (Morris Water Maze)

In vivo Model for Cholinergic Inhibition. 18 Male rats (Wistar, 250-300g) were injected intracerebroventricularly (i.c.v.) at a rate of 0.21μl/min., using plastic tubing (PE-20) attached to 25G needle; controlsreceived an injection of saline 2 μl/side, experimental animals receivedinjections of the cholinergic blocker (ethylcholine aziridium) AF64A (3nmol/2 μl/side).

Drug treatment was initiated 7-10 days after AF64A injection. Animalswere divided into two equal groups. Test group received daily nasaladministration of St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) dissolved in 10%Sefsol™ and 40% isopropanol at a concentration of 10 μg/40 μl (20 μladministered through each nostril). Control animals received intranasaladministration of the vehicle. The rats were partially anesthetized bydiethylether prior to nasal administration. Following seven days of drugadministration, behavioral assays were conducted for an additional 10days. Drugs were applied by nasal administration 1 hour prior totesting. All animals were chronically treated (every two days) with50,000 units of durabiotic antibiotics to avoid infection.

Learning test procedure was carried out according to the Morris WaterMaze procedure (Morris et al., Nature, 297:681-683, 1982; Morris et al.,Nature, 319:774-776, 1986).

1. Administration of St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6)

Rats were placed in a circular pool, 1.26 m in diameter, 0.2 m deep,equipped with a clear plexiglas column, with a 13.3 cm platform reachingjust below the surface of the water (22-24° C). Drugs were applied dailyby nasal administration 1 hour prior to testing. The latency of reachingthe platform was recorded for each rat (in seconds) and the changes overdays of training were graphed, which reflect learning and memory.

As can be seen in FIG. 2, control animals injected with AF64A (◯) showeda smaller improvement in the latency of reaching the platforms comparedwith animals injected with AF64A and nasally administered withSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) (). These results indicate thatthe conjugate of the invention is able to improve learning and memory inan animal model of Alzheimer.

II. Administration of St-Lys-Lys-Tyr-D-Ala-NH₂

FIG. 3 depicts the effects of St-Lys-Lys-Tyr-D-Ala-NH₂ (indicated KKYOin the figure) on learning and memory in the Alzheimer's in vivo test(AF64A-cholinotoxicity test) as described above. The results obtainedwere similar to those described above with control animals which weretreated only with AF64A () showed smaller improvement in the latency ofreaching the platforms compared with animals nasally administered alsowith St-Lys-Lys-Tyr-D-Ala-NH₂ (▴). An additional probe test was alsoperformed (Gozes et al., Proc. Nat. Acad. Sci. USA 93:427-432, 1996), inthis test: after the animals know where the platform is in the waterpool, the platform is removed and the time the animals spend in the areaoccupied before by the platform is recorded, this time periodsrepresents memory retention of a previously studied test. As observed inFIG. 4, St-Lys-Lys-Tyr-D-Ala-NH₂ treated animals exhibit better memoryretention than the AF64A treated animals that did not receive thepeptide. Following this test the platform is placed back in the waterpool, but this time it is visible to the swimming rat and the timerequired to reach it is measured. In this case the parameter measured ispossible motor deficits. As can be seen in FIG. 5, there are nodifferences between the groups, thus overall, the test measured learningand memory and not motor changes.

EXAMPLE C3

Effects of a Conjugate of the Invention on Learning and Memory of NormalAnimals

The experiment described in Example C2 was repeated but the animals wereinjected with saline instead of with AF64A and thus were normal animals,not featuring Alzheimer-like cognitive damages. The animals were dividedinto two groups, one administered intranasally only with the vehicle(Sefsol+isopropanol as described above) and one receiving intranasaladministration of St-Lys-Lys-Tyr-D-Ala-NH₂. As can be seen in FIG. 6, anapparent somewhat faster learning was observed in the peptide treatedgroup indicating a possible improvement of cognitive function also inundamaged, normal animals.

EXAMPLE C4

Effects of a Conjugate of the Invention on a Model for Memory Retention

A new model was developed in order to assess the capability of animalsto retain the memory of a previously learned test. Animals (N=5-10) werefirst taught to find a submerged platform in a water maze as describedabove. For assessment of memory retention, the animals were subjected todaily swim (a test a day) in order to learn to find the hidden platform.After a week, the animals which showed the highest score in the studytest, were chosen for the experiment. AF64A or saline were injected intothe third ventricle of the brain and following a week of recuperation,the animals were treated by intranasal administration of the peptideSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) as described above. Following aweek of peptide treatment, the animals were tested again in the watermaze and the experiment of retention of the learned task (i.e. findingthe platform) was repeated as follows: the animal was placed on aplatform for 1 min. And then placed in the water for swimming to theplatform and the time required to reach the platform was measured. Theresults of the first swim are summarized in FIG. 7. As can be seen inthe figure, it is evident that animals treated with the peptide areprotected from memory loss, and are capable of retaining the memory ofthe task studied previous to the injection with AF64A since they behavein a similar manner to control.

After 1 min. on the platform, the animal is placed back in the water foran additional swim and search of the hidden platform. FIG. 8 shows theresult for the second swim. As can be seen, FIG. 8 also shows animprovement in learning and memory in animals treated with the peptide.This model, is the first demonstration of the activity of the peptideand facilitating memory retention.

Finally, the platform is removed and the time spent by the animals atthe area where the platform is featured in FIG. 9. The resultssummarized above, clearly demonstrate that St-Lys-Lys-Tyr-Leu-NH₂ (SEQID NO:6) is involved in learning, in working memory, and in memoryretention.

EXAMPLE C5

Effect of Conjugates of the Invention on a Model for Mental Retardation

A Model for Mental Retardation: Apolipoprotein E-deficient Mice

It has recently been discovered that mice deficient in apolipoprotein E(ApoE) (Plump et al., Cell, 71:343-363 (1992)) are retarded in theiracquisition of developmental milestones. The ApoE deficient mice weretested for the development of behavioral milestones and were found to besignificantly retarded in their acquisition of forelimb placing behavior(postnatal day 11-13) as compared to control animals (postnatal day2-5). A two day delay in the acquisition of cliff aversion behavior alsowas observed in these mice.

8 newborn normal mice were injected (s.c. 1.2 μg 120 μu) withSt-Lys-Lys-Tyr-Leu-NH₂ or with saline. 8 ApoE deficient newborn micewere treated similarly.

The results of forelimb placing behavior acquisition are shown in FIGS.10 and 11. As can be seen ApoE deficient mice treated withSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) or with the known St-Nle¹⁷-VIP-NH₂(shown for comparison only) St-Nle¹⁷-VIP improved their placingacquisition essentially to the level of control as compared withuntreated ApoE deficient mice.

FIGS. 12 and 13 show cliff avoidance acquisition in animals treated asabove. As can be seen, ApoE deficient mice treated withSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) or St-Nle-V1P -NH₂ (shown forcomparison only) showed even better cliff avoidance acquisition thannormal controls or similar cliff avoidance behavior to control.

EXAMPLE C6

Effect of a Conjugate of the Invention on the Cholinergic Activity inApolipoprotein E Deficient Mice

Apo-E deficient mice were assayed for their cholinergic activity asdescribed by Fonnum, F. A., J Neurochem., 24:413-415, 1975. Briefly,brains from 21 days normal (control) and ApoE-deficient mice wereassessed by measuring their Chat activity. Choline acetyl transferase(Chat) activity was determined as described before (see text), bymeasurements of the rate of synthesis of (14Cqacctylcholine from cholineand [14C]acetylCoA. Non-specific background was measured in the absenceof choline. Each brain (300-400 mg) was homogenized in a teflonhomogenizer, with 10 volumes of 50 mM phosphate buffer (pH=7.4)containing 300 mM NaCl, 30 mM EDTA and 0.5% triton. The homogenates werecentrifuged at 12000 g for 15 min., and 10 141 of the supernatant (intriplicates) were mixed with 10 μl of a solution containing: 14 μM14C-acetyl-CoA (56 mCi/mmol NEN), 20 mM Acetylcholine, 1.6 mM cholinechloride, 0.25 mM eserine, and phosphate buffer. The reaction wascarried out at 37° C. for 15 min. stopped by adding 50 μl of 15 mg/mltetraphenylboron prepared in 3-heptanone and mixed in a vortex for 30sec. Twenty μl of the organic phase were collected after 2 min.microfuging, then were mixed with scintillation liquid and radioactivitywas measured in a beta-counter.

Experiments were conducted on 21-day-old animals chronically injectedwith peptides or with saline. Injection is performed subcutaneously,peptides are dissolved (100 μg/30 μl) in DMSO and diluted with saline toobtain the desired concentrations. Day 1-4: 4 μg peptide/20 μl saline;day 5-10: 8 μg/40 μl saline; day 11-14: 16 μg/80 μl saline.

The results of cholinergic activity show a reduction in Apo-E deficientmice. The cholinergic activity of mice administered withSt-Lys-Lys-Tyr-Leu (SEQ ID NO:6), are shown in FIG. 14. The figuredemonstrates ApoE mice treated with St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6)which show an increase in choline acetyl transferase activity ascompared to the control levels.

FIG. 14 indicate that St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) increasescholinergic activity in the apolipoprotcin E deficient mice (100%activity indicates 669-758 pmole/mg, protein/min. in all thedeterminations of choline acetyl transferase activity).

EXAMPLE C7

Biodistribution of St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6)

St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) was radioiodinated by using thechloramine T methods as described in Gozes et al., Endocrinology,134:2121-2125 (1994) and about 7.8×10⁶ cpm/2 μl 5% Sefsol™, 20%isopropanol/rat were applied intranasally to 250-300 g rats. Animalswere sacrificed 30 minutes following drug administration and the frontalcortex was removed, weighed and counted for radioactivity in a gammacounter. Radioactive tissue samples (containing 1400 cpm/gram sample)were thereafter homogenized and subjected to centrifugation (5,400 g for25 min.). Supernatants were then subjected to HPLC analysis againstSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) as a marker (eluting using anacetonitrile gradient at fraction 25). Samples were monitored forradioactivity in a gamma counter.

As can be seen in FIG. 15, intact St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6)could be observed in the brain thirty minutes after application,indicating that the conjugates of the invention, when administeredintranasally are able to reach the brain.

D. The Impotence Prevention Aspect of the Invention

Biological Tests for Penile Reflexes

The biological tests involved measurements of penile reflexes incastrated rats following transdermal application of the conjugates ofthe invention. In a first type of biological experiment the effects ofcompositions with various carriers on penile reflexes were measured andit was found that Sefsol™ was the most effective carrier.

(a) Methods

Animal Model for Impotence

Rats with reduced sexual potential due to castration were employed. Malerats (250-300 g, about three months old) were kept in a 12-hours light,12-hours dark cycle. Experiments were always conducted within the darkperiod, 2-6 hours after the onset of darkness. Male rats were castratedand given partial testosterone replacement (4 μg/100 g body weight) inthe form of daily injection during 14-21 consecutive days (the durationof the experiment). Experiments were conducted one week followingsurgery.

Direct Evaluation of Penile Reflexes (Erections)

A procedure was utilized that employed the technique that measuressexual reflexes in the penis, which enables direct evaluation of penileerection following transdermal administration of the drug. Successfulreproduction depends, in large part, upon the precise execution oftemporally organized, functionally related behavioral units. In theseexperiments, we concentrated on the final stages of the erection process(reddening of the penis accompanied by its distension and extensionleading to complete erection) and monitored the latency time to thefirst E2 and first cup (Okumura, M., et al., Chem. Pharm. Bull. 37, 1375(1989)).

For testing, each animal was restrained in a supine position with theanterior portion of its body enclosed in a loosely fitting cylinder (7cm diam.). After a belt was secured around the torso, the glans peniswas extruded from its sheath and gently held perpendicular to theabdomen by a thin wooden applicator positioned at the posterior of thepenis. The legs of the male were held by the observer and this positionwas maintained throughout the test period. The duration of the sessionwas 45 minutes. The latencies and numbers of E2 and cups were recordedand plotted.

An E2 is defined as a complete erection which can be followed by cup inwhich the penile tip is turned into a cup-like structure, whereby theglands flare out such that the penis is wider in its distal portion thanits base. This final stage requires E2 and is probably a pre-requisitefor ejaculation. Using all the parameters one can obtain a reliablemeasure of the sexual activity of the tested rat.

Duration of ES2 was determined by monitoring animals for a period of 45minutes and calculating total time of erection whether by measuring thelength of a single erection episode or by adding together severalnon-continuous erection episodes. The minimal duration of a singleerection episode was calculated as half a minute.

EXAMPLE D1

Effect of the Conjugates of the Invention in a Rat Model of Impotence

Conjugates were dissolved in dimethylsulfoxide (DMSO) at a concentrationof 10⁻³M and 10 μl were utilized per application. Rats used werecastrated-treated by partial testosterone replacement (Gozes et al., J.Clin. Inves., 90:810-814 (1992)). In short, male rats (90-100 days old)were castrated and immediately injected daily with 4 μg/100 g BWtestosterone, s.c. for 21 consecutive days, the duration of theexperiment. Experiments were initiated one week after surgery. Penilereflexes were measured as described above.

FIG. 16 shows that peptide 6(St-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:24) wasable to significantly improve both number of cups and the number of E2as compared to control. FIG. 17 depicts peptide 6 in comparison topeptide 26. Experiments were repeated for the other conjugates of theinvention substantially as described above, but peptides were dissolvedin 5% Sefsol™ and 20% isopropanol to a final concentration of 7 μg/10 μlper animal. The conjugates tested were: St-Lys-Lys-Tyr-Leu-NH₂ (SEQ IDNO:6); St-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:25);St-Asn-Ser-Ile-Tyr-Leu-Asn-NH₂ (SEQ ID NO:74); St-Lys-Lys-Tyr-D-Ala-NH₂;St-Lys-Lys-Tyr-Val-NH₂ (SEQ ID NO:9); St-Lys-Lys-Tyr-Leu-Nle-NH₂ (SEQ IDNO:10); St-Lys-Lys-Tyr-Leu-Pro-Pro-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ IDNO:73).

The results are shown in FIGS. 18-27 and indicate that all testedconjugates were able to improve all tested impotence parameters whichwere determined (No. of cups, No. of E2 and reduction of latency to thefirst cup) as compared to control.

EXAMPLE D2

Biodistribution Following Topical Administration ofSt-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6)

St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6) was radioiodinated as before andabout 2.2×10⁶ cpm/2 μl 5% Sefsol™, 20% isopropanol/rat were appliedtopically on the sex organ of 250-300 g rats. Animals were sacrificed atindicated times and tissues were weighed and counted for radioactivityin a gamma counter.

The results are shown in FIG. 28. These results indicate that conjugateswhich were administered transdermally were able to penetrate the innertissue of the animal.

EXAMPLE D3

HPLC Analysis of Intestinal Extract

Experiment was performed as indicated in Example D2. Animals weresacrificed 30 minutes following drug administration and the intestinewas removed weighed and counted for radioactivity in a gamma counter.Radioactive tissue samples were thereafter homogenized and subjected tocentrifugation (5,400 g for 25 min.). Supernatants were then subjectedto HPLC analysis against radiolodinated St-Lys-Lys-Tyr-Leu-NH₂ (SEQ IDNO:6) as a marker (eluting using an acetonitrile gradient at fraction25). Samples were monitored for radioactivity in a gamma counter.

The results are shown in FIG. 29. As can be seen from the results inFIGS. 26 and 27 of the applied 2.2×10⁶ cpm/g more than 80,000 cpm/g werelocated in the intestine 30 mins. following application. By comparison,using the same amounts of radiolabeled St-Nle¹⁷-VIP only 3700 cpm/g wereobtained in the intestine (Gozes et al., Endocrinology, 134:2121-2125(1994)) showing that the short conjugate of the invention has a muchbetter penetration than the full 28 amino acid conjugate.

EXAMPLE D4

Effect of the Conjugates of the Invention in a Rabbit Model of Impotence

New Zealand white rabbits (from Yokneam, Israel) were anesthetized withRompun and Ketavet. Additionally, pentobarbital 10 mg/kg, i.v. wasadministered into an ear vein. Anesthesia was maintained by bolusinjections of pentobarbital (5-10 mg/kg). The animals were placed in asupine position on an operating table, in a temperature-regulatedenvironment. The area around the penis was shaved and a 20 gauge needlewas inserted into the left or right corpus cavernosum and the catheterconnected to a pressure transducer for a continuous recording of theintracavarnosal (i.c.) pressure. The transducer amplifier used was ModelPM-1000 (CWE incorporated); System 1000 power supply (CWE incorporated);Software: DI 200 PGH/PGL (DATA Q Instrument Inc.). When injection wasrequired, a second catheter was placed into the other side of the corpuscavernosum for the administration of the drugs, both catheters werefilled with blood. The catheter for blood pressure recording was flushedwith 0.5 ml 2% heparin. Increases in the i.c. blood pressure areexpressed on the graphs as mm Hg.

FIG. 30 shows preliminary results of change of pressure obtained withinjections of St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6), in the corpuscavernosum. Here 10 μg showed increased activity, with penile bloodpressure increasing to 75 mmHg (from 15-20 mmHg) indicating that thisconjugate can effect penile erection also by direct injection.

E. Pharmaceutical Compositions for Transdermal Applications

An example of ointment composition for transdermal application oflipophilic conjugated peptides in accordance with the present inventionwith Sefsol 318™ as a carrier comprises: 1 mg peptide per 714 μl 10%Sefsol 318™ (glyceryl monocaprylate) and 714 , μl 40% isopropanol (finalconcentrations: 5% Sefsol, 20% isopropanol and about 0.7 mg/ml peptide).

SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 80 <210> SEQ ID NO: 1 <211>LENGTH: 28 <212> TYPE: PRT <213> ORGANISM: HOMO SAPIENS <400> SEQUENCE:1 His Ser Asp Ala Val Phe Tyr Asp Asn Tyr Thr Arg Leu Arg Lys Gln 1 5 1015 Met Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn 20 25 <210> SEQ IDNO: 2 <211> LENGTH: 25 <212> TYPE: PRT <213> ORGANISM: Unknown <220>FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: Any one orall of residues 1, 2 and 3 may be present or absent; residue 1 is Ala,Val, or absent; residue 2 is Ala, Val, or absent; residue 3 is Ala, Val,Lys, D-Lys, Orn or absent; one of residues 1, 2, 3 or 4 is theN-terminal residue, and may be modified with a lipophilic moiety;residue 4 is Lys, D-Lys, or Orn; residue 5 is Tyr, D-Tyr, Phe, Trp, orp-amino Phe; residue 6 is a hydrophobic amino acid residue; any one orall of residues 7-11 may be present or absent; residue 7 is Asn, Ser,Ile, Tyr, Leu, Nle, D-Ala, or absent; residue 8 is Ser or absent;residue 9 is Ile, Tyr, or absent; residue 10 is Leu or absent; residue11 is Asn or absent; any one or all of residues 12-25 may be present orabsent; residue 12 is a Ser, Asn, a hdrophobic aliphatic amino acidresidue, Tyr, Lys, Val, Ala, a non-charged amino acid residue, orabsent; residue 13 is Ile, Tyr, Asn, a hydrophobic aliphatic amino acidresidue, Lys, D-Lys, Orn, Ala, Val, a non- charged amino acid residue,or absent; residue 14 is Leu, Asn, a hydrophobic aliphatic amino acidresidue, Tyr, Lys, a non-charged amino acid residue, Ala, Val, D-Lys,Orn, D-Tyr, Phe, Trp, p-amino Phe, or absent; residue 15 is Asn, ahydrophobic aliphatic amino acid residue, Tyr, Lys, D-Lys, Orn, D-Tyr,Phe, Trp, p-amino Phe, Ala, Val, or absent; residue 16 is Asn, ahydrophobic aliphatic amino acid residue, Tyr, Lys, Val, Ala, D-Tyr,Phe, Trp, p-amino Phe, Nle, Leu, Ile, Ser, D-Ala, D-Lys, Orn, or absent;residue 17 is a hydrophobic aliphatic amino acid residue, Lys, D-Lys,Orn, Asn, Ser, Ile, Leu, Tyr, Nle, D-Ala, D-Tyr, Phe, Trp, p-amino Phe,or absent; residue 18 is Asn, Lys, D-Lys, Orn, Tyr, D-Tyr, Phe, Trp,p-amino Phe, Ser, Ile, Leu, Nle, D-Ala, a hydrophobic aliphatic aminoacid residue, or absent; residue 19 is Ser, Tyr, D-Tyr, Phe, Trp,p-amino Phe, a hydrophobic aliphatic amino acid residue, Ile, Leu, Asn,Nle, D-Ala, or absent; residue 20 is Ile, Tyr, Ser, Asn, Leu, ahydrophobic aliphatic amino acid residue, Nle, D-Ala, or absent; residue21 is Leu, Ile, Tyr, Asn, Ser, Nle, D-Ala, or absent; residue 22 is Asn,Ile, Tyr, Ser, Leu, or absent; residue 23 is Asn, Leu, Ile, Tyr, orabsent; residue 24 is Asn, Leu, or absent; residue 25 is Asn or absent;the C-terminal residue is amidated or modified with a lipophilic moiety.<400> SEQUENCE: 2 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa XaaXaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 <210>SEQ ID NO: 3 <211> LENGTH: 25 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: Any one orall of residues 1-7 may be present or absent; residue 1 is Val, Ala, orabsent; residue 2 is Val, Ala, or absent; residue 3 is Lys, Val, orabsent; residue 4 is Lys or absent; residue 5 is Tyr, Lys, or absent;residue 6 is a hydrophobic aliphatic amino acid residue, Tyr, Lys, orabsent; residue 7 is Asn, a hydrophobic aliphatic amino acid residue, orabsent; residue 9 is Ile or Tyr; any one or all of residues 12-25 may bepresent or absent; residue 12 is a Ser, Asn, a hdrophobic aliphaticamino acid residue, Tyr, Lys, Val, Ala, a non-charged amino acidresidue, or absent; residue 13 is Ile, Tyr, Asn, a hydrophobic aliphaticamino acid residue, Lys, D-Lys, Orn, Ala, Val, a non- charged amino acidresidue, or absent; residue 14 is Leu, Asn, a hydrophobic aliphaticamino acid residue, Tyr, Lys, a non-charged amino acid residue, Ala,Val, D-Lys, Orn, D-Tyr, Phe, Trp, p-amino Phe, or absent; residue 15 isAsn, a hydrophobic aliphatic amino acid residue, Tyr, Lys, D-Lys, Orn,D-Tyr, Phe, Trp, p-amino Phe, Ala, Val, or absent; residue 16 is Asn, ahydrophobic aliphatic amino acid residue, Tyr, Lys, Val, Ala, D-Tyr,Phe, Trp, p-amino Phe, Nle, Leu, Ile, Ser, D-Ala, D-Lys, Orn, or absent;residue 17 is a hydrophobic aliphatic amino acid residue, Lys, D-Lys,Orn, Asn, Ser, Ile, Leu, Tyr, Nle, D-Ala, D-Tyr, Phe, Trp, p-amino Phe,or absent; residue 18 is Asn, Lys, D-Lys, Orn, Tyr, D-Tyr, Phe, Trp,p-amino Phe, Ser, Ile, Leu, Nle, D-Ala, a hydrophobic aliphatic aminoacid residue, or absent; residue 19 is Ser, Tyr, D-Tyr, Phe, Trp,p-amino Phe, a hydrophobic aliphatic amino acid residue, Ile, Leu, Asn,Nle, D-Ala, or absent; residue 20 is Ile, Tyr, Ser, Asn, Leu, ahydrophobic aliphatic amino acid residue, Nle, D-Ala, or absent; residue21 is Leu, Ile, Tyr, Asn, Ser, Nle, D-Ala, or absent; residue 22 is Asn,Ile, Tyr, Ser, Leu, or absent; residue 23 is Asn, Leu, Ile, Tyr, orabsent; residue 24 is Asn, Leu, or absent; residue 25 is Asn or absent;the C-terminal residue is amidated or modified with a lipophilic moiety.<400> SEQUENCE: 3 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Ser Xaa Leu Asn Xaa XaaXaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 <210>SEQ ID NO: 4 <211> LENGTH: 25 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: Residue 1 isAsp, Glu, Cys, Orn, Lys, or an amino acid with a side chain of-(CH2)2NH3, and residue 1 may be modified with a lipophilic moiety;residues 1 and 6 are linked by a -CO-NH-, -NH-CO-, -S-S-,-S(CH2)tCO-NH-, or -NH-CO(CH2)tS- bond; residue 5 is a hydrophobicaliphatic amino acid residue; residue 6 is Asp, Glu, Cys, Orn, Lys, oran amino acid with a side chain of -(CH2)2NH3; any one or all ofresidues 7-11 may be present or absent; residue 7 is Asn, Ser, Ile, Tyr,Leu, or absent; residue 8 is Ser or absent; residue 9 is Ile, Tyr, orabsent; residue 10 is Leu or absent; residue 11 is Asn or absent; anyone or all of residues 12-25 may be present or absent; residue 12 is aSer, Asn, a hdrophobic aliphatic amino acid residue, Tyr, Lys, Val, Ala,a non-charged amino acid residue, or absent; residue 13 is Ile, Tyr,Asn, a hydrophobic aliphatic amino acid residue, Lys, D-Lys, Orn, Ala,Val, a non- charged amino acid residue, or absent; residue 14 is Leu,Asn, a hydrophobic aliphatic amino acid residue, Tyr, Lys, a non-chargedamino acid residue, Ala, Val, D-Lys, Orn, D-Tyr, Phe, Trp, p-amino Phe,or absent; residue 15 is Asn, a hydrophobic aliphatic amino acidresidue, Tyr, Lys, D-Lys, Orn, D-Tyr, Phe, Trp, p-amino Phe, Ala, Val,or absent; residue 16 is Asn, a hydrophobic aliphatic amino acidresidue, Tyr, Lys, Val, Ala, D-Tyr, Phe, Trp, p-amino Phe, Nle, Leu,Ile, Ser, D-Ala, D-Lys, Orn, or absent; residue 17 is a hydrophobicaliphatic amino acid residue, Lys, D-Lys, Orn, Asn, Ser, Ile, Leu, Tyr,Nle, D-Ala, D-Tyr, Phe, Trp, p-amino Phe, or absent; residue 18 is Asn,Lys, D-Lys, Orn, Tyr, D-Tyr, Phe, Trp, p-amino Phe, Ser, Ile, Leu, Nle,D-Ala, a hydrophobic aliphatic amino acid residue, or absent; residue 19is Ser, Tyr, D-Tyr, Phe, Trp, p-amino Phe, a hydrophobic aliphatic aminoacid residue, Ile, Leu, Asn, Nle, D-Ala, or absent; residue 20 is Ile,Tyr, Ser, Asn, Leu, a hydrophobic aliphatic amino acid residue, Nle,D-Ala, or absent; residue 21 is Leu, Ile, Tyr, Asn, Ser, Nle, D-Ala, orabsent; residue 22 is Asn, Ile, Tyr, Ser, Leu, or absent; residue 23 isAsn, Leu, Ile, Tyr, or absent; residue 24 is Asn, Leu, or absent;residue 25 is Asn or absent; the C-terminal residue is amidated ormodified with a lipophilic moiety. <400> SEQUENCE: 4 Xaa Lys Lys Tyr XaaXaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa XaaXaa Xaa Xaa Xaa Xaa 20 25 <210> SEQ ID NO: 5 <211> LENGTH: 25 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: Any one or all of residues 1-6 may be presentor absent; one of residues 1-6 is the N-terminal residue and may bemodified with a lipophilic moiety; residue 1 is Ala or absent; residue 2is Val, Ala, or absent; residue 3 is Lys or absent; residue 4 is Lys orabsent; residue 5 is Tyr, Lys, or absent; residue 6 is a hydrophobicaliphatic amino acid residue, Tyr, Lys, or absent; residue 7 is Asp,Glu, Cys, Orn, Lys, or an amino acid with a side chain of -(CH2)2NH3;residues 7 and 13 are linked by a -CO-NH-, -NH-CO-, -S-S-,-S(CH2)tCO-NH-, or -NH-CO(CH2)tS- bond; residue 8 is Asn or absent;residue 10 is Ile or Tyr; residue 13 is Asp, Glu, Cys, Orn, Lys, or anamino acid with a side chain of -(CH2)2NH3; any one or all of residues14-27 may be present or absent; residue 14 is a Ser, Asn, a hdrophobicaliphatic amino acid residue, Tyr, Lys, Val, Ala, a non-charged aminoacid residue, or absent; residue 15 is Ile, Tyr, Asn, a hydrophobicaliphatic amino acid residue, Lys, D-Lys, Orn, Ala, Val, a non- chargedamino acid residue, or absent; residue 16 is Leu, Asn, a hydrophobicaliphatic amino acid residue, Tyr, Lys, a non-charged amino acidresidue, Ala, Val, D-Lys, Orn, D-Tyr, Phe, Trp, p-amino Phe, or absent;residue 17 is Asn, a hydrophobic aliphatic amino acid residue, Tyr, Lys,D-Lys, Orn, D-Tyr, Phe, Trp, p-amino Phe, Ala, Val, or absent; residue18 is Asn, a hydrophobic aliphatic amino acid residue, Tyr, Lys, Val,Ala, D-Tyr, Phe, Trp, p-amino Phe, Nle, Leu, Ile, Ser, D-Ala, D-Lys,Orn, or absent; residue 19 is a hydrophobic aliphatic amino acidresidue, Lys, D-Lys, Orn, Asn, Ser, Ile, Leu, Tyr, Nle, D-Ala, D-Tyr,Phe, Trp, p-amino Phe, or absent; residue 20 is Asn, Lys, D-Lys, Orn,Tyr, D-Tyr, Phe, Trp, p-amino Phe, Ser, Ile, Leu, Nle, D-Ala, ahydrophobic aliphatic amino acid residue, or absent; residue 21 is Ser,Tyr, D-Tyr, Phe, Trp, p-amino Phe, a hydrophobic aliphatic amino acidresidue, Ile, Leu, Asn, Nle, D-Ala, or absent; residue 22 is Ile, Tyr,Ser, Asn, Leu, a hydrophobic aliphatic amino acid residue, Nle, D-Ala,or absent; residue 23 is Leu, Ile, Tyr, Asn, Ser, Nle, D-Ala, or absent;residue 24 is Asn, Ile, Tyr, Ser, Leu, or absent; residue 25 is Asn,Leu, Ile, Tyr, or absent; residue 26 is Asn, Leu, or absent; residue 27is Asn or absent; the C-terminal residue is amidated or modified with alipophilic moiety. <400> SEQUENCE: 5 Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa SerXaa Leu Asn Xaa Xaa Xaa Xaa 1 5 10 15 Xaa Xaa Xaa Xaa Xaa Xaa Xaa XaaXaa 20 25 <210> SEQ ID NO: 6 <211> LENGTH: 4 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 6 Lys Lys Tyr Leu 1 <210> SEQ ID NO: 7 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The N-terminus is modified with astearoyl moiety; the C-terminal residue is amidated. <400> SEQUENCE: 7Ala Val Lys Lys Tyr Leu 1 5 <210> SEQ ID NO: 8 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The N-terminus is modified with a stearoylmoiety; the C-terminal residue is amidated. <400> SEQUENCE: 8 Asn SerIle Leu Asn 1 5 <210> SEQ ID NO: 9 <211> LENGTH: 4 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 9 Lys Lys Tyr Val 1 <210> SEQ ID NO: 10 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The N-terminus is modified with astearoyl moiety; the C-terminal residue is amidated; residue 5 is Nle.<400> SEQUENCE: 10 Lys Lys Tyr Leu Xaa 1 5 <210> SEQ ID NO: 11 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The N-terminus is modified with astearoyl moiety; the C-terminal residue is amidated. <400> SEQUENCE: 11Asn Ser Tyr Leu Asn 1 5 <210> SEQ ID NO: 12 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The N-terminus is modified with a stearoyl moiety; theC-terminal residue is amidated. <400> SEQUENCE: 12 Asn Ser Ile Tyr Asn 15 <210> SEQ ID NO: 13 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 13 Lys Lys Tyr Leu Pro Pro Asn Ser Ile Leu Asn1 5 10 <210> SEQ ID NO: 14 <211> LENGTH: 4 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a lauroyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 14 Lys Lys Tyr Leu 1 <210> SEQ ID NO: 15 <211>LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The N-terminus is modified with acaproyl moiety; the C-terminal residue is amidated. <400> SEQUENCE: 15Lys Lys Tyr Leu 1 <210> SEQ ID NO: 16 <211> LENGTH: 4 <212> TYPE: PRT<213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The N-terminus is modified with a stearoyl moiety; theC-terminal residue is amidated; residue 4 is Nle. <400> SEQUENCE: 16 LysLys Tyr Xaa 1 <210> SEQ ID NO: 17 <211> LENGTH: 5 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 17 Val Lys Lys Tyr Leu 1 5 <210> SEQ ID NO: 18<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE:<223> OTHER INFORMATION: Description of Unknown Organism:Artificial<220> FEATURE: <223> OTHER INFORMATION: The N-terminus is modified witha stearoyl moiety; the C-terminal residue is amidated. <400> SEQUENCE:18 Leu Asn Ser Ile Leu Asn 1 5 <210> SEQ ID NO: 19 <211> LENGTH: 7 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The N-terminus is modified with a stearoylmoiety; the C-terminal residue is amidated. <400> SEQUENCE: 19 Tyr LeuAsn Ser Ile Leu Asn 1 5 <210> SEQ ID NO: 20 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The N-terminus is modified with a stearoyl moiety; theC-terminal residue is amidated. <400> SEQUENCE: 20 Lys Lys Tyr Leu Asn 15 <210> SEQ ID NO: 21 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 21 Lys Lys Tyr Leu Asn Ser 1 5 <210> SEQ IDNO: 22 <211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Unknown <220>FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 22 Lys Lys Tyr Leu Asn Ser Ile 1 5 <210> SEQID NO: 23 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Unknown <220>FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 23 Lys Lys Tyr Leu Asn Ser Ile Leu 1 5 <210>SEQ ID NO: 24 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; <400> SEQUENCE: 24 Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn1 5 10 <210> SEQ ID NO: 25 <211> LENGTH: 4 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 25 Ser Ile Leu Asn 1 <210> SEQ ID NO: 26 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The N-terminus is modified with acaproyl moiety; the C-terminal residue is amidated; residues 5 and 6 areaminocaproic acid or D-Leu. <400> SEQUENCE: 26 Lys Lys Tyr Leu Xaa Xaa 15 <210> SEQ ID NO: 27 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a lauroyl moiety;the C-terminal residue isamidated; residue 5 is aminocaproic acid or D-Leu. <400> SEQUENCE: 27Lys Lys Tyr Leu Xaa 1 5 <210> SEQ ID NO: 28 <211> LENGTH: 5 <212> TYPE:PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The C-terminal residue is amidated; residue 5 isaminocaproic acid or D-Leu. <400> SEQUENCE: 28 Lys Lys Tyr Leu Xaa 1 5<210> SEQ ID NO: 29 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheC-terminal residue is amidated; residues 5 and 6 are aminocaproic acidor D-Leu. <400> SEQUENCE: 29 Lys Lys Tyr Leu Xaa Xaa 1 5 <210> SEQ IDNO: 30 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Unknown <220>FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheC-terminal residue is amidated; residue 5 is aminolauric acid or D-Lys.<400> SEQUENCE: 30 Lys Lys Tyr Leu Xaa 1 5 <210> SEQ ID NO: 31 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The C-terminal residue is amidated;residues 5-7 are aminocaproic acid or D-Leu. <400> SEQUENCE: 31 Lys LysTyr Leu Xaa Xaa Xaa 1 5 <210> SEQ ID NO: 32 <211> LENGTH: 6 <212> TYPE:PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The N-terminus is modified with a lauroyl moiety; TheC-terminal residue is amidated; residue 6 is aminocaproic acid or D-Leu.<400> SEQUENCE: 32 Asn Ser Ile Leu Asn Xaa 1 5 <210> SEQ ID NO: 33 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The C-terminal residue is amidated;residue 6 is aminocaproic acid or D-Leu. <400> SEQUENCE: 33 Asn Ser IleLeu Asn Xaa 1 5 <210> SEQ ID NO: 34 <211> LENGTH: 7 <212> TYPE: PRT<213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The C-terminal residue is amidated; residues 6 and 7 areaminocaproic acid or D-Leu. <400> SEQUENCE: 34 Asn Ser Ile Leu Asn XaaXaa 1 5 <210> SEQ ID NO: 35 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a caproyl moiety; the C-terminal residue isamidated; residues 6 and 7 are aminocaproic acid or D-Leu. <400>SEQUENCE: 35 Asn Ser Ile Leu Asn Xaa Xaa 1 5 <210> SEQ ID NO: 36 <211>LENGTH: 8 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The C-terminal residue is amidated;residues 6-8 are aminocaproic acid or D-Leu. <400> SEQUENCE: 36 Asn SerIle Leu Asn Xaa Xaa Xaa 1 5 <210> SEQ ID NO: 37 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The C-terminal residue is amidated; residue 6is aminolauric acid or D-Lys. <400> SEQUENCE: 37 Asn Ser Ile Leu Asn Xaa1 5 <210> SEQ ID NO: 38 <211> LENGTH: 10 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheC-terminal residue is amidated; residue 5 is aminocaproic acid or D-Leu.<400> SEQUENCE: 38 Lys Lys Tyr Leu Xaa Asn Ser Ile Leu Asn 1 5 10 <210>SEQ ID NO: 39 <211> LENGTH: 11 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheC-terminal residue is amidated; residues 5 and 6 are aminocaproic acidor D-Leu. <400> SEQUENCE: 39 Lys Lys Tyr Leu Xaa Xaa Asn Ser Ile Leu Asn1 5 10 <210> SEQ ID NO: 40 <211> LENGTH: 12 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheC-terminal residue is amidated; residues 5-7 are aminocaproic acid orD-Leu. <400> SEQUENCE: 40 Lys Lys Tyr Leu Xaa Xaa Xaa Asn Ser Ile LeuAsn 1 5 10 <210> SEQ ID NO: 41 <211> LENGTH: 10 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheC-terminal residue is amidated; residue 5 is aminolauric acid or D-Lys.<400> SEQUENCE: 41 Lys Lys Tyr Leu Xaa Asn Ser Ile Leu Asn 1 5 10 <210>SEQ ID NO: 42 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; residues 5-7 are Ala, D-Ala or p-amino Phe. <400> SEQUENCE: 42Lys Lys Tyr Leu Xaa Xaa Xaa Asn Ser Ile Leu Asn 1 5 10 <210> SEQ ID NO:43 <211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Unknown <220>FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 43 Lys Lys Leu Tyr Ala Ala Ala Asn Ser Ile LeuAsn 1 5 10 <210> SEQ ID NO: 44 <211> LENGTH: 10 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 44 Lys Lys Tyr Leu Pro Asn Ser Ile Leu Asn 1 510 <210> SEQ ID NO: 45 <211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 45 Lys Tyr Leu Asn Ser Ile Leu Asn 1 5 <210>SEQ ID NO: 46 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 46 Lys Lys Tyr Leu Asn Ser Ile Leu Asn 1 5<210> SEQ ID NO: 47 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a lauroyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 47 Lys Lys Tyr Leu Asn Ser Ile Leu Asn 1 5<210> SEQ ID NO: 48 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 48 Lys Tyr Leu Asn 1 <210> SEQ ID NO: 49 <211>LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: The N-terminus is modified with astearoyl moiety; the C-terminal residue is amidated; residue 5 is D-Alaor D-Tyr. <400> SEQUENCE: 49 Lys Lys Tyr Leu Xaa 1 5 <210> SEQ ID NO: 50<211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE:<223> OTHER INFORMATION: Description of Unknown Organism:Artificial<220> FEATURE: <223> OTHER INFORMATION: The N-terminus is modified witha stearoyl moiety; the C-terminal residue is amidated. <400> SEQUENCE:50 Lys Lys Tyr Leu Leu 1 5 <210> SEQ ID NO: 51 <211> LENGTH: 4 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The N-terminus is modified with a stearoylmoiety; the C-terminal residue is amidated; residue 2 is aminolauricacid or D-Lys. <400> SEQUENCE: 51 Lys Xaa Tyr Leu 1 <210> SEQ ID NO: 52<211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE:<223> OTHER INFORMATION: Description of Unknown Organism:Artificial<220> FEATURE: <223> OTHER INFORMATION: The N-terminus is modified witha stearoyl moiety; the C-terminal residue is amidated; residue 1 isaminolauric acid or D-Lys. <400> SEQUENCE: 52 Xaa Lys Tyr Leu 1 <210>SEQ ID NO: 53 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; residues 1 and 2 are aminolauric acid or D-Lys. <400>SEQUENCE: 53 Xaa Xaa Tyr Leu 1 <210> SEQ ID NO: 54 <211> LENGTH: 4 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The N-terminus is modified with a stearoylmoiety; the C-terminal residue is amidated. <400> SEQUENCE: 54 Lys LysPhe Leu 1 <210> SEQ ID NO: 55 <211> LENGTH: 4 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; residue 4 is aminocaproic acid or D-Leu. <400> SEQUENCE: 55Lys Lys Tyr Xaa 1 <210> SEQ ID NO: 56 <211> LENGTH: 4 <212> TYPE: PRT<213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The N-terminus is modified with a stearoyl moiety; theC-terminal residue is amidated. <400> SEQUENCE: 56 Lys Lys Trp Leu 1<210> SEQ ID NO: 57 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; residue 3 is Ala, D-Ala or p-amino Phe. <400> SEQUENCE: 57 LysLys Xaa Leu 1 <210> SEQ ID NO: 58 <211> LENGTH: 4 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; residue 2 is Orn. <400> SEQUENCE: 58 Lys Xaa Tyr Leu 1 <210>SEQ ID NO: 59 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; residue 1 is Orn. <400> SEQUENCE: 59 Xaa Lys Tyr Leu 1 <210>SEQ ID NO: 60 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; residues 1 and 2 are Orn. <400> SEQUENCE: 60 Xaa Xaa Tyr Leu 1<210> SEQ ID NO: 61 <211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a oleic acid moiety; the C-terminal residueis amidated. <400> SEQUENCE: 61 Lys Lys Tyr Leu 1 <210> SEQ ID NO: 62<211> LENGTH: 4 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE:<223> OTHER INFORMATION: Description of Unknown Organism:Artificial<220> FEATURE: <223> OTHER INFORMATION: The N-terminus is modified witha propyl moiety; the C-terminal residue is amidated. <400> SEQUENCE: 62Lys Lys Tyr Leu 1 <210> SEQ ID NO: 63 <211> LENGTH: 10 <212> TYPE: PRT<213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The N-terminus is modified with a stearoyl moiety; theC-terminal residue is amidated. <400> SEQUENCE: 63 Lys Lys Tyr Leu AlaAla Lys Lys Tyr Leu 1 5 10 <210> SEQ ID NO: 64 <211> LENGTH: 10 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The N-terminus is modified with a stearoylmoiety; the C-terminal residue is amidated. <400> SEQUENCE: 64 Lys LysTyr Leu Pro Pro Lys Lys Tyr Leu 1 5 10 <210> SEQ ID NO: 65 <211> LENGTH:9 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The N-terminus is modified with a stearoylmoiety; the C-terminal residue is amidated; residue 5 is aminocaproicacid. <400> SEQUENCE: 65 Lys Lys Tyr Leu Xaa Lys Lys Tyr Leu 1 5 <210>SEQ ID NO: 66 <211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Unknown<220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated; residue 5 is aminolauric acid. <400> SEQUENCE: 66 Lys Lys TyrLeu Xaa Lys Lys Tyr Leu 1 5 <210> SEQ ID NO: 67 <211> LENGTH: 5 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The N-terminus is modified with a stearoylmoiety; the C-terminal residue is amidated. <400> SEQUENCE: 67 Lys LysTyr Leu Leu 1 5 <210> SEQ ID NO: 68 <211> LENGTH: 5 <212> TYPE: PRT<213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The N-terminus is modified with a caproyl moiety; theC-terminal residue is amidated. <400> SEQUENCE: 68 Asn Ser Ile Leu Asn 15 <210> SEQ ID NO: 69 <211> LENGTH: 5 <212> TYPE: PRT <213> ORGANISM:Unknown <220> FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a lauroyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 69 Asn Ser Ile Leu Asn 1 5 <210> SEQ ID NO: 70<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE:<223> OTHER INFORMATION: Description of Unknown Organism:Artificial<220> FEATURE: <223> OTHER INFORMATION: The N-terminus is modified witha stearoyl moiety; the C-terminal residue is amidated. <400> SEQUENCE:70 Lys Lys Lys Tyr Leu Asp 1 5 <210> SEQ ID NO: 71 <211> LENGTH: 6 <212>TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: The N-terminus is modified with a stearoylmoiety; the C-terminal residue is amidated. <400> SEQUENCE: 71 Cys LysLys Tyr Leu Cys 1 5 <210> SEQ ID NO: 72 <211> LENGTH: 6 <212> TYPE: PRT<213> ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION:Description of Unknown Organism:Artificial <220> FEATURE: <223> OTHERINFORMATION: The N-terminus is modified with a stearoyl moiety; theC-terminal residue is amidated. <400> SEQUENCE: 72 Cys Lys Lys Tyr LeuLys 1 5 <210> SEQ ID NO: 73 <211> LENGTH: 6 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 73 Leu Asn Ser Ile Leu Asn 1 5 <210> SEQ IDNO: 74 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Unknown <220>FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: TheN-terminus is modified with a stearoyl moiety; the C-terminal residue isamidated. <400> SEQUENCE: 74 Asn Ser Ile Tyr Leu Asn 1 5 <210> SEQ IDNO: 75 <211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Unknown <220>FEATURE: <223> OTHER INFORMATION: Description of UnknownOrganism:Artificial <220> FEATURE: <223> OTHER INFORMATION: Xaa atposition 1 is a residue of a hydrophobic aliphatic amino acid <400>SEQUENCE: 75 Xaa Asn Ser Ile Leu Asn 1 5 <210> SEQ ID NO: 76 <211>LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: Xaa at position 1 is a residue of ahydrophobic aliphatic amino acid <400> SEQUENCE: 76 Xaa Asn Ser Tyr LeuAsn 1 5 <210> SEQ ID NO: 77 <211> LENGTH: 7 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: Xaaat position 6 is a residue of a hydrophobic aliphatic amino acid <400>SEQUENCE: 77 Val Ala Lys Lys Tyr Xaa Asn 1 5 <210> SEQ ID NO: 78 <211>LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223>OTHER INFORMATION: Description of Unknown Organism:Artificial <220>FEATURE: <223> OTHER INFORMATION: Xaa at position 6 is a residue of ahydrophobic aliphatic amino acid <400> SEQUENCE: 78 Ala Val Lys Lys TyrXaa Asn 1 5 <210> SEQ ID NO: 79 <211> LENGTH: 11 <212> TYPE: PRT <213>ORGANISM: Unknown <220> FEATURE: <223> OTHER INFORMATION: Description ofUnknown Organism:Artificial <220> FEATURE: <223> OTHER INFORMATION: Anyone or all of residues 1-7 may be present or absent; residue 1 is Val,Ala, or absent; residue 2 is Val, Ala, or absent; residue 3 is Lys, Val,or absent; residue 4 is Lys or absent; residue 5 is Tyr, Lys, or absent;residue 6 is a hydrophobic aliphatic amino acid residue, Tyr, Lys, orabsent; residue 7 is Asn, a hydrophobic aliphatic amino acid residue, orabsent; residue 9 is Ile or Tyr; the C-terminal residue is amidated ormodified with a lipophilic moiety. <400> SEQUENCE: 79 Xaa Xaa Xaa XaaXaa Xaa Xaa Ser Xaa Leu Asn 1 5 10 <210> SEQ ID NO: 80 <211> LENGTH: 11<212> TYPE: PRT <213> ORGANISM: Unknown <220> FEATURE: <223> OTHERINFORMATION: Description of Unknown Organism:Artificial <220> FEATURE:<223> OTHER INFORMATION: Any one or all of residues 1, 2 and 3 may bepresent or absent; residue 1 is Ala, Val, or absent; residue 2 is Ala,Val, or absent; residue 3 is Ala, Val, Lys, D-Lys, Orn or absent; one ofresidues 1, 2, 3 or 4 is the N-terminal residue, and may be modifiedwith a lipophilic moiety; residue 4 is Lys, D-Lys, or Orn; residue 5 isTyr, D-Tyr, Phe, Trp, or p-amino Phe; residue 6 is a hydrophobic aminoacid residue; any one or all of residues 7-11 may be present or absent;residue 7 is Asn, Ser, Ile, Tyr, Leu, Nle, D-Ala, or absent; residue 8is Ser or absent; residue 9 is Ile, Tyr, or absent; residue 10 is Leu orabsent; residue 11 is Asn or absent; the C-terminal residue is amidatedor modified with a lipophilic moiety. <400> SEQUENCE: 80 Xaa Xaa Xaa XaaXaa Xaa Xaa Xaa Xaa Xaa Xaa 1 5 10

What is claimed is:
 1. A conjugate of a peptide coupled to a lipophilic moiety, wherein the peptide has at least 3 and at most 12 amino acid residues, said conjugate being selected from the formulae: (i) R₁-X₁-X₁′-X₁″-X₂-NH—R₂ (SEQ ID NO:2); (ii) R₁-X₃-Ser-X₄-Leu-Asn-NH—R₂ (SEQ ID NO:3);

wherein R₁ is H or a lipophilic moiety; R₂ is H, a lipophilic moiety, a lipophilic moiety substituted by X₃-Ser-X₄-Leu-Asn-NHR₁ (SEQ ID NO:79) or a spacer consisting of 1-3 residues of a non-charged amino acid coupled to X₁-X₁′-X₁″-X₂-NHR₁ (SEQ ID NO:80), with the proviso that at least one of R₁ and R₂ is a lipophilic moiety; X₁ is a covalent bond, Ala, Val, Ala-Val, Val-Ala, L-Lys, D-Lys, Ala-Lys, Val-Lys, Ala-Val-Lys; Val-Ala-Lys or Orn; X₁′ is L-Lys, D-Lys or Orn; X₁″ is L-Tyr, D-Tyr, Phe, Trp or the residue of p-amino phenylalanine; X₄ is Ile or Tyr; X₅ is a residue of a hydrophobic aliphatic amino acid; X₂ is X₅, X₅-Asn, X₅-Ser, X₅-Ile, X₅-Tyr, X₅-Leu, X₅-Nle, X₅-D-Ala, X₅-Asn-Ser, X₅-Asn Ser-Ile (residues 1-4 of SEQ ID NO:75), X₅-Asn-Ser-Tyr (residues 1-4 of SEQ ID NO:76), X₅-Asn-Ser-Ile-Leu (residues 1-5 of SEQ ID NO:75), X₅-Asn-Ser-Tyr-Leu (residues 1-5 of SEQ ID NO:76), X₅-Asn-Ser-Tyr-Leu (residues 1-5 of SEQ ID NO:76), X₅-Asn-Ser-Ile-Leu-Asn (SEQ ID NO:75) or X₅-Asn-Ser-Tyr-Leu-Asn (SEQ ID NO:76); X₃ is a covalent bond, Asn, X₅, X₅-Asn, Tyr-X₅, Tyr-X₅-Asn, Lys-X₅, Lys-X₅-Asn, Lys-Tyr-X₅, Lys-Tyr-X₅-Asn (residues 4-7 of SEQ ID NO:77), Lys-Lys-Tyr-X₅ (residues 3-6 of SEQ ID NO:77), Lys-Lys-Tyr-X₅-Asn (residues 3-7 of SEQ ID NO:77), Val-Lys-Lys-Tyr-X₅ (residues 2-6 of SEQ ID NO:78), Val-Ala-Lys-Lys-Tyr-X₅-Asn (SEQ ID NO:77), or Ala-Val-Lys-Lys-Tyr-X₅-Asn (SEQ ID NO:78); X₆ is a covalent bond or Asn, Ser, Ile, Tyr, Leu, Asn-Ser, Asn-Ser-Ile, Asn-Ser-Tyr, Asn-Ser-Ile-Leu (residues 2-5 of SEQ ID NO:75), Asn-Ser-Tyr-Leu (residues 2-5 of SEQ ID NO:76), Asn-Ser-Ile-Leu-Asn (residues 2-6 of SEQ ID NO:75) or Asn-Ser-Tyr-Leu-Asn (residues 2-6 of SEQ ID NO:76); X₇ is a covalent bond or Asn; X₈ is a covalent bond, X₅, Tyr, Lys, Tyr-X₅, Lys-X₅, Lys-Tyr-X₅, Lys-Lys-Tyr-X₅ (residues 3-6 of SEQ ID NO:77), Val-Lys-Lys-Tyr-X₅ (residues 2-6 of SEQ ID NO:78), Ala-Lys-Lys-Tyr-X₅ (residues 2-6 of SEQ ID NO:77), or Ala-Val-Lys-Lys-Tyr-X₅ (residues 1-6 of SEQ ID NO:78); Z is —CONH—, NHCO—, —S—S—, —S(CH₂)_(t)CO—NH— or —NH—CO(CH₂)_(t)S—; m is 1 or 2 when Z is —CONH—, —S—S— or —S(CH₂)_(t)CO—NH—, or m is 2, 3 or 4 when Z is —NH—CO— or —NH—CO(CH₂)_(t)S—; n is 1 or 2 when Z is —NH—CO—, —S—S— or —NH—CO(CH₂)_(t)S—, or n is 2, 3 or 4 when Z is —CONH— or —S(CH₂)_(t)CO—NH—, and t is 1 or 2, with the proviso that the conjugate stearoyl-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:24) is excluded.
 2. A conjugate according to claim 1, wherein X₅ is a residue of an D- or L-amino acid selected from Ala, Ile, Leu, Met, Val, Nva and Nle.
 3. A conjugate according to claim 1, wherein the lipophilic moiety R₁ is a saturated or unsaturated hydrocarbyl or carboxylic acyl radical having at least 5 carbon atoms.
 4. A conjugate according to claim 3, wherein R₁ is selected from: stearoyl (ST), caproyl (Cap) and lauroyl (Lau).
 5. A conjugat according to claim 4, selected from the group consisting of: St-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:6); St-Lys-Lys-Tyr-D-Ala-NH₂; St-Ala-Val-Lys-Lyl-Tyr-Leu-NH₂ (SEQ ID NO:7); St-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:8); St-Lys-Lys-Tyr-Leu-Nle-NH₂ (SEQ ID NO:10); St-Lys-Lys-Tyr-Val-NH₂ (SEQ ID NO:9); and St-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:25).
 6. A conjugate according to claim 4, selected from the group consisting of: St-Asn-Ser-Tyr-Leu-Asn-NH₂ (SEQ ID NO:11); St-Asn-Ser-Ile-Tyr-Asn-NH₂ (SEQ ID NO:12); and St-Lys-Lys-Tyr-Leu-Pro-Pro-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:13).
 7. A conjugat according to claim 4, selected from the group consisting of: Lau-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:14); Cap-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:15); St-Lys-Tyr-Leu-NH₂; St-Lys-Lys-Tyr-Nle-NH₂ (SEQ ID NO:16); St-Val-Lys-Lys-Tyr-Leu-NH₂ (SEQ ID NO:17); St-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:18); St-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:19); St-Lys-Lys-Tyr-Leu-Asn-NH₂ (SEQ ID NO:20); St-Lys-Lys-Tyr-Leu-Asn-Ser-NH₂ (SEQ ID NO:21); St-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-NH₂ (SEQ ID NO:22); and St-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-NH₂ (SEQ ID NO:23).
 8. A pharmaceutical composition comprising as an active ingredient a conjugate according to claim 1, together with a pharmaceutically acceptable carrier.
 9. A pharmaceutical composition for the treatment of neurodegenerative diseases comprising as an active ingredient a conjugate selected from the group consisting of a conjugate according to claims 5 or
 7. 10. A pharmaceutical composition according to claim 9, wherein the neurodegenerative disease is selected form the group consisting of: Alzheimer's disease, Down Syndrome, decline in motor or cognitive function due to ischemia, stroke, hereditary disease of the central and peripheral nervous system, decline in motor or cognitive function due to injury of the central or peripheral nervous system and neuronal disorder associated with blood circulation and neuronal survival.
 11. A pharmaceutical composition according to claim 9, suitable for nasal administration.
 12. A pharmaceutical composition according to claim 11, in the form of a nasal spray.
 13. A pharmaceutical composition for the treatment of sexual disfunctions, comprising as an active ingredient a conjugate selected from thy group consisting of a conjugate according to claim 6, St-Lys-Lys-Tyr-D-Ala-NH₂, St-Lys-Lys-Tyr-Leu-Nle-NH₂ (SEQ ID NO: 10), and St-Lys-Lys-Tyr-Val-NH₂ (SEQ ID NO:9) together with a pharmaceutically acceptable carrier.
 14. A pharmaceutical composition according to claim 10, for the treatment of male impotence.
 15. A pharmaceutical composition according to claim 13, adapted for transdermal application.
 16. A pharmaceutical composition according to claim 15, wherein the pharmaceutically acceptable carrier is 1-glyceryl monocaprylate.
 17. A method for treating sexual disfunction, comprising administering a conjugate selected from the group consisting of a conjugate according to claim 5, a conjugate according to claim 6, and conjugate St-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:24) to a patient in need thereof.
 18. The method of claim 17, wherein the sexual disfunction is male impotence.
 19. The method of claim 17, wherein the conjugate is formulated for transdermal administration.
 20. The method of claim 17, wherein the conjugate is St-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH₂ (SEQ ID NO:24) and is combined with 1-glyceryl monocaprylate as a carrier.
 21. A method for treating a neurodegenerative disease, comprising administering a conjugate selected from the group consisting of a conjugate according to claim 6, St-Lys-Lys-Tyr-D-Ala-NH₂, St-Lys-Lys-Tyr-Leu-Nle-NH₂ (SEQ ID NO:10), and St-Lys-Lys-Tyr-Val-NH₂ (SEQ ID NO:11) to a patient in need thereof.
 22. The method of claim 21, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Down Syndrome, decline in motor or cognitive function due to ischemia, stroke, hereditary disease of the central and peripheral nervous system, decline in motor or cognitive function due to injury of the central or peripheral nervous system, and neuronal disorder associated with blood circulation and neuronal survival.
 23. The method of claim 21, wherein the conjugate is administered nasally.
 24. The method of claim 21, wherein the conjugate is formulated for administration in the form of a nasal spray. 